CN103933555B - Stable digestive enzyme compositions - Google Patents

Stable digestive enzyme compositions Download PDF

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Publication number
CN103933555B
CN103933555B CN201410059861.7A CN201410059861A CN103933555B CN 103933555 B CN103933555 B CN 103933555B CN 201410059861 A CN201410059861 A CN 201410059861A CN 103933555 B CN103933555 B CN 103933555B
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composition
lipase
dosage form
coated
cellulose
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CN201410059861.7A
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CN103933555A (en
Inventor
乔瓦尼.奥滕齐
马科.马科尼
卢吉.马佩利
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Erjian Medical Co ltd
Elastagen Pty Ltd
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Aptalis Pharma Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/465—Hydrolases (3) acting on ester bonds (3.1), e.g. lipases, ribonucleases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4826—Trypsin (3.4.21.4) Chymotrypsin (3.4.21.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y301/00—Hydrolases acting on ester bonds (3.1)
    • C12Y301/01—Carboxylic ester hydrolases (3.1.1)
    • C12Y301/01003—Triacylglycerol lipase (3.1.1.3)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

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  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Enzymes And Modification Thereof (AREA)

Abstract

The present composition comprising at least one digestive ferment (such as pancreatic lipase) can be used for treating or preventing and digesting the relevant disease of azymia.The composition of the present invention can include a variety of coated particles, each described particle is made of enteric-coated core, the enteric coating includes at least one enteric polymer and 4 10% at least one basifier, or the composition has about 3% or smaller water capacity or about 0.6 or smaller water activity or the loss of activity that no more than about 15% is shown after the accelerated stability test of six months.

Description

Stable digestive enzyme compositions
The application is the Chinese invention patent application (applying date：On 2 20th, 2008；Application number：200880012762.6 (international application no：PCT/IB2008/000770)；Denomination of invention：Stable digestive enzyme compositions) divisional application.
Cross reference to related applications
This application claims the U.S. Provisional Applications submitted for 20th for 2 months in 2007 to submit for 20 days 2 months 60/902,091,2007 year 60/902,093 and 2007 year U.S. Provisional Application 60/902,092 submitted for 20th for 2 months of U.S. Provisional Application priority, Their disclosures are hereby incorporated by reference for all purposes herein.
Background technology
In the case of pancreas insufficient (pancreatic insufficiency), pancreatic lipase can be administered (pancrelipase) and other pancreatin products (pancreatic enzyme product, PEP), so as to right at least partly By various diseases (such as pancreatitis, pancreatectomy (pancreatectomy), the cystic fibrosis of influence pancreas (pancreas) (cystic fibrosis) etc.) caused by azymia treated.Purposes of the pancreatin in pancreas insufficiency is treated is to control Treat vital part in cystic fibrosis patient.In the case of these no supplements (supplement), Huan Zhehui There is serious nutrition defect.This nutrition defect (nutritional impairment) may be to have if without treatment Life danger, particularly in the case of baby.
Drug substance (drug substance) pancreatic lipase is mainly three fermentoids i.e. lipase (lipase), protease (protease) and the combination of amylase (amylase) and their various co-factors (co-factor) and coenzyme.These enzymes It is natively generated in pancreas, and is important in the digestion of fat, protein and carbohydrate.Pancreatic lipase typical case Ground is prepared from pig pancreas, although other sources can also be used, such as in U.S.6,051,220, U.S.2004/0057944, Every document, is incorporated herein by reference by those sources described in 2001/0046493 and WO2006044529 herein.The enzyme It is glycerine and aliphatic acid to be catalyzed fat splitting, and catalytic starch is hydrolyzed to dextrin and sugar and catalytic proteins are hydrolyzed to amino acid With derivative substance.
Pancreatin close to it is neutral and slightly alkalescence under conditions of show optimal activity.Under the conditions of stomach, pancreatin can quilt Inactivation, wherein causing the loss of bioactivity.Therefore, the enzyme of usual exogenous administration is protected, and is made it that stomach not occur and is gone out (gastric inactivation) living and keep complete during it is by stomach and into duodenum.Although it is contemplated that be Pancreatin is coated, but uncoated preparation is existed in business.Pancreatic lipase is most sensitive in stomach inactivation, and It is most important single enzyme in the treatment of malabsorption (malabsorption).Usually the activity of lipase is monitored To determine the stability of the enzymatic compositions containing lipase.
After by stomach, the enzyme can discharge in duodenum in 5-30 minutes, this is because while digestion and inhale Receipts can be happened at gastrointestinal tract everywhere, but the digestion and the absorption of metabolin carried out by pancreatin occurs mainly in the epimere of intestines (upper segment).Usually by pancreatin enteric coatings polymer coating, the enteric coatings polymer protective enzyme group Closing object makes it be not exposed in stomach acidity environment, then provides release of the enzyme in intestines.
Conventional pancreatinum is inherently unstable, and without the oral medication produce usually with being ratified The product relevant shelf life.The activity of pancreatinum is typically based on the activity of lipase to determine, and during lipase is storage One of enzyme most sensitive to loss enzymatic activity.Commercially available digestive enzyme compositions are shown as time go by is up to about 35% or more More lipase active losses.In order to compensate for enzymatic activity between storage period loss and ensure that product carries in the later stage of shelf life For nominal effect, manufacturer usually carries out dosage form excessive filling (excess is 5% to 60%), and currently for pancreas fat The U.S. pharmacopoeia specification (USP specification) of enzyme sustained release capsule allow pancreatic lipase be equivalent to no less than 90% and Not more than 165% indicates lipase active.
In practice it means that patient and prescriptionist cannot judge dose intensity exactly, wherein actual result It is to need by virtue of experience to determine appropriate dosage for each new prescription.With pancreatic exocrine insufficiency illness It is suitable that the patient of (exocrine pancreatic insufficiency disorder) provides them dependent on these drugs When the enzyme needed for digestion food.If label contains the inaccurate description for being related to specific product effect, patient, which meets, to be bordered by having received The danger of more or very few drug.
Therefore, it should it is desirable that, provide be able to maintain that for the expectation shelf life of enzyme preparation needed for activity without Dependent on the stabilization digestive enzyme compositions excessively filled to dosage form.
The content of the invention
The present invention relates to stable digestive enzyme compositions and dosage form and the methods for preparing stable enzymatic compositions and dosage form. More particularly it relates to enteric-coated (enteric coated) enzymatic compositions and dosage form, the enzymatic compositions and Dosage form shows the loss of activity of very little under typical storage requirement.
In one embodiment, the present invention provides the composition for including at least one digestive ferment, wherein the combination Object has about 3% or smaller water capacity (moisture content).
In another embodiment, composition of the invention includes at least one digestive ferment, wherein the composition has There is about 0.6 or smaller water activity (water activity).
In another embodiment, composition of the invention includes at least one stabilized digestive ferment, wherein institute State the activity damage that at least one stabilized digestive ferment shows no more than about 15% after the accelerated stability test of six months It loses.
In another embodiment, the present invention provides the dosage form filled with the present composition, such as tablet or capsule Agent.
In another embodiment, composition of the invention also includes at least one digestive ferment for being surrounded by coating, wherein The coating includes enteric polymer (enteric polymer) and optionally at least one inorganic material (inorganic material)。
In another embodiment, the present invention provides a kind of packaging, it includes by barrier material (moisture Resistant material) made of sealing container, drier (dessicant) and the present invention at least one dosage form, Described in drier and at least one dosage form on the inside of the sealing container.
In another embodiment, the present invention provides treat or prevent and digestion azymia (digestive Enzyme deficiency) relevant illness method, the described method includes give the composition of the present invention to this needs Mammal.
In another embodiment, the present invention provides the methods for preparing the present composition.In an embodiment In, the described method includes be about 3.6g water/m in water capacity3Or with comprising enteric polymer and at least one in smaller atmosphere The coating of kind inorganic material is coated the particle of at least one digestive ferment, is consequently formed a variety of delayed release granules (delayed release particle)。
In particular it relates to herein below：
1. a kind of compositions of item, it includes at least one digestive ferment, wherein the composition has about 3% or smaller to contain Moisture.
The composition that item is 2. 1, wherein the water capacity is about 2% or smaller.
The composition that item is 3. 1, wherein at least one digestive ferment is selected from pancreatic lipase, lipase, trypsase, gruel Protease, chymotrypsin B, pancreas peptase, Carboxypeptidase A, protaminase, glycerol ester hydrolase, phosphatidase, phospholipase A2, sterol ester water Solve enzyme, ribalgilase, deoxyribonuclease, alpha-amylase, papain, chymopapain, bromelain, Ficin, beta amylase, cellulase, beta galactosidase and their mixture.
The composition that item is 4. 3, wherein at least one digestive ferment is lipase.
The composition that item is 5. 3, wherein at least one digestive ferment is pancreatic lipase.
The composition that item is 6. 4, wherein the lipase is animal tallow enzyme, comprising lipase of bacterial origin, fungal lipase, plant Lipase, recombinant lipase, synthetic lipase, the lipase through chemical modification or their mixture.
The composition that item is 7. 1, also comprising at least one pharmaceutical excipient.
The composition of 8. 7, wherein at least one pharmaceutical excipient is selected from adhesive, disintegrant, lubricant, helps Flow agent, diluent and their mixture.
The composition that item is 9. 7, wherein at least one pharmaceutical excipient is selected from following at least one stabilizer： Trehalose, proline, glucan, maltose, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and their mixing Object.
The composition that item is 10. 7, wherein at least one pharmaceutical excipient is selected from following at least one bonding Agent：Starch, sugar, lactose, sugar alcohol, xylitol, D-sorbite, maltitol, cellulose, microcrystalline cellulose, modified cellulose, hydroxyl Propyl cellulose, sodium carboxymethylcellulose, alginic acid and polyvinylpyrrolidone.
The composition that item is 11. 7, wherein at least one pharmaceutical excipient is selected from following at least one disintegration Agent：Calcium monohydrogen phosphate, dicalcium phosphate dihydrate, calcium phosphate, cornstarch, alginic acid, hydroxypropyl cellulose, carboxymethyl cellulose Calcium, sodium carboxymethylcellulose, croscarmellose sodium, swellable ion exchange resin, alginate, formaldehyde-casein, Cellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, microcrystalline cellulose, sodium carboxymethyl starch, sodium starch glycollate, starch And rice starch.
The composition that item is 12. 7, wherein at least one pharmaceutical excipient is selected from following at least one lubrication Agent：Calcium stearate, magnesium stearate, Sodium stearyl fumarate, stearic acid, zinc stearate, talcum and wax.
The composition that item is 13. 7, wherein at least one pharmaceutical excipient is to help stream selected from following at least one Agent：Colloidal silicon dioxide and talcum.
The composition that item is 14. 7, wherein at least one pharmaceutical excipient is selected from following at least one dilution Agent：Mannitol, sucrose, calcium phosphate dibasic anhydrous, calcium phosphate dibasic anhydrous dihydrate, calcium phosphate, cellulose, lactose, magnesium carbonate and Microcrystalline cellulose.
The composition that item is 15. 1, wherein the composition shows lipase compared with composition of the water capacity more than 3% The larger stability of activity.
Item 16. includes the composition of at least one digestive ferment, wherein the composition is lived with about 0.6 or smaller water Property.
The composition that item is 17. 16, wherein the water activity is about 0.4 or smaller.
The composition of 18. 16, wherein at least one digestive ferment be selected from pancreatic lipase, lipase, trypsase, Chymotrypsin, chymotrypsin B, pancreas peptase, Carboxypeptidase A, protaminase, glycerol ester hydrolase, phosphatidase, phospholipase A2, sterol ester Hydrolase, ribalgilase, deoxyribonuclease, alpha-amylase, papain, chymopapain, bromelain Enzyme, ficin, beta amylase, cellulase, beta galactosidase and their mixture.
The composition that item is 19. 18, wherein at least one digestive ferment is lipase.
The composition that item is 20. 18, wherein at least one digestive ferment is pancreatic lipase.
The composition that item is 21. 19, wherein the lipase is animal tallow enzyme, comprising lipase of bacterial origin, fungal lipase, plant Object lipase, recombinant lipase, synthetic lipase, the lipase through chemical modification or their mixture.
The composition that item is 22. 16, also comprising at least one pharmaceutical excipient.
The composition of 23. 22, wherein at least one pharmaceutical excipient be selected from adhesive, disintegrant, lubricant, Glidant, diluent and their mixture.
The composition that item is 24. 22, wherein at least one pharmaceutical excipient is to stablize selected from following at least one Agent：Trehalose, proline, glucan, maltose, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and they Mixture.
The composition that item is 25. 22, wherein at least one pharmaceutical excipient is selected from following at least one bonding Agent：Starch, sugar, lactose, sugar alcohol, xylitol, D-sorbite, maltitol, cellulose, microcrystalline cellulose, modified cellulose, hydroxyl Propyl cellulose, sodium carboxymethylcellulose, alginic acid and polyvinylpyrrolidone.
The composition that item is 26. 22, wherein at least one pharmaceutical excipient is selected from following at least one disintegration Agent：Calcium monohydrogen phosphate, dicalcium phosphate dihydrate, calcium phosphate, cornstarch, alginic acid, hydroxypropyl cellulose, carboxymethyl cellulose Calcium, sodium carboxymethylcellulose, croscarmellose sodium, swellable ion exchange resin, alginate, formaldehyde-casein, Cellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, microcrystalline cellulose, sodium carboxymethyl starch, sodium starch glycollate, starch And rice starch.
The composition that item is 27. 22, wherein at least one pharmaceutical excipient is selected from following at least one lubrication Agent：Calcium stearate, magnesium stearate, Sodium stearyl fumarate, stearic acid, zinc stearate, talcum and wax.
The composition that item is 28. 22, wherein at least one pharmaceutical excipient is to help stream selected from following at least one Agent：Colloidal silicon dioxide and talcum.
The composition that item is 29. 22, wherein at least one pharmaceutical excipient is selected from following at least one dilution Agent：Mannitol, sucrose, calcium phosphate dibasic anhydrous, calcium phosphate dibasic anhydrous dihydrate, calcium phosphate, cellulose, lactose, magnesium carbonate and Microcrystalline cellulose.
The composition that item is 30. 22, wherein at least one stabilizer is selected from trehalose, proline, glucan, malt Sugar, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and their mixture.
The composition that item is 31. 16, wherein the composition shows fat compared with composition of the water activity more than 0.6 The larger stability of enzymatic activity.
Item 32. includes the composition of at least one digestive ferment, wherein acceleration of at least one digestive ferment at six months The digestive enzyme activity loss no more than 15% is shown after stability test.
The composition that item is 33. 32, wherein at least one digestive ferment is shown after trimestral accelerated stability test Show that the digestive enzyme activity no more than 10% loses.
The composition that item is 34. 32, wherein the accelerated stability test is included in 40 DEG C/75% relative humidity by described in Composition is stored 3 months in the Nialene bags of sealing.
The composition of 35. 32, wherein at least one digestive ferment be selected from pancreatic lipase, lipase, trypsase, Chymotrypsin, chymotrypsin B, pancreas peptase, Carboxypeptidase A, protaminase, glycerol ester hydrolase, phosphatidase, phospholipase A2, sterol ester Hydrolase, ribalgilase, deoxyribonuclease, alpha-amylase, papain, chymopapain, bromelain Enzyme, ficin, beta amylase, cellulase, beta galactosidase and their mixture.
The composition that item is 36. 35, wherein at least one digestive ferment is lipase.
The composition that item is 37. 35, wherein at least one digestive ferment is pancreatic lipase.
The composition that item is 38. 36, wherein the lipase is animal tallow enzyme, comprising lipase of bacterial origin, fungal lipase, plant Object lipase, recombinant lipase, synthetic lipase, the lipase through chemical modification or their mixture.
The composition that item is 39. 30, also comprising at least one pharmaceutical excipient.
The composition of 40. 39, wherein at least one pharmaceutical excipient be selected from adhesive, disintegrant, lubricant, Glidant, diluent and their mixture.
The composition that item is 41. 39, wherein at least one pharmaceutical excipient is to stablize selected from following at least one Agent：Trehalose, proline, glucan, maltose, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and they Mixture.
The composition that item is 42. 39, wherein at least one pharmaceutical excipient is selected from following at least one bonding Agent：Starch, sugar, lactose, sugar alcohol, xylitol, D-sorbite, maltitol, cellulose, microcrystalline cellulose, modified cellulose, hydroxyl Propyl cellulose, sodium carboxymethylcellulose, alginic acid and polyvinylpyrrolidone.
The composition that item is 43. 39, wherein at least one pharmaceutical excipient is selected from following at least one disintegration Agent：Calcium monohydrogen phosphate, dicalcium phosphate dihydrate, calcium phosphate, cornstarch, alginic acid, hydroxypropyl cellulose, carboxymethyl cellulose Calcium, sodium carboxymethylcellulose, croscarmellose sodium, swellable ion exchange resin, alginate, formaldehyde-casein, Cellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, microcrystalline cellulose, sodium carboxymethyl starch, sodium starch glycollate, starch And rice starch.
The composition that item is 44. 39, wherein at least one pharmaceutical excipient is selected from following at least one lubrication Agent：Calcium stearate, magnesium stearate, Sodium stearyl fumarate, stearic acid, zinc stearate, talcum and wax.
The composition that item is 45. 39, wherein at least one pharmaceutical excipient is to help stream selected from following at least one Agent：Colloidal silicon dioxide and talcum.
The composition that item is 46. 39, wherein at least one pharmaceutical excipient is selected from following at least one dilution Agent：Mannitol, sucrose, calcium phosphate dibasic anhydrous, calcium phosphate dibasic anhydrous dihydrate, calcium phosphate, cellulose, lactose, magnesium carbonate and Microcrystalline cellulose.
A kind of 47. dosage forms of item, tablet or capsule including the composition containing item 1.
The dosage form that item is 48. 47, wherein the dosage form is the capsule of the composition filled with item 1.
The dosage form that item is 49. 48, it includes：
There are many capsules of coated particle for filling；
The coated particle includes enteric-coated core；
The core includes pancreatic lipase and at least one disintegrant；And
The enteric coating include at least one enteric polymer and based on coating total weight for 20-60%wt.% at least A kind of basifier；
There is wherein described coated particle about 3% or smaller water capacity and the capsule to have 4% or smaller Water capacity.
The dosage form that item is 50. 49, wherein the capsule has about 2% or smaller water content.
The dosage form that item is 51. 48, wherein the capsule is formed by being selected from following substance：Cellulosic polymer, hydroxypropyl Methylcellulose, starch, polysaccharide, pullulan and gelatin.
The dosage form that item is 52. 51, wherein the capsule includes hydroxypropyl methyl cellulose.
The dosage form that item is 53. 49, wherein the capsule includes hydroxypropyl methyl cellulose.
A kind of 54. dosage forms of item include the capsule of the composition filled with item 16.
The dosage form that item is 55. 54, wherein the capsule has about 2% or smaller water content.
The dosage form that item is 56. 54, wherein the capsule is formed by being selected from following substance：Cellulosic polymer, hydroxypropyl Methylcellulose, starch, polysaccharide, pullulan and gelatin.
The dosage form that item is 57. 56, wherein the capsule includes hydroxypropyl methyl cellulose.
A kind of 58. dosage forms of item include the capsule of the composition filled with item 32.
The dosage form that item is 59. 58, wherein the capsule has the water content less than 2%.
The dosage form that item is 60. 58, wherein the capsule is formed by being selected from following substance：Cellulosic polymer, hydroxypropyl Methylcellulose, starch, polysaccharide, pullulan and gelatin.
The dosage form that item is 61. 60, wherein the capsule includes hydroxypropyl methyl cellulose.
The composition that item is 62. 1, wherein at least one digestive ferment is surrounded by coating, and the coating includes enteric Property polymer.
The composition that item is 63. 62, wherein the coating is also comprising at least one inorganic material.
The composition that item is 64. 63, wherein the enteric polymer and inorganic material are with about 4:1 to about 1:25 ratio In the presence of.
The composition that item is 65. 62, wherein the enteric polymer is selected from Cellacefate, adjacent benzene two Formic acid hydroxypropyl methyl cellulose, hydroxypropylmethylcellulose acetate succinate, poly- acetate phthalate vinyl acetate, methyl-prop Olefin(e) acid-methylmethacrylate copolymer and shellac.
The composition that item is 66. 64, wherein at least one inorganic material includes basifier.
The composition that item is 67. 66, wherein the basifier is selected from talcum, silica, sodium salt, calcium salt, magnesium salts, aluminium Salt, aluminium hydroxide, calcium hydroxide, magnesium hydroxide and their mixture.
The composition that item is 68. 62, wherein the coating also includes plasticizer.
The composition of 69. 68, wherein the plasticizer be selected from glyceryl triacetate, tributyl citrate, triethyl citrate, Acetoxyl group tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor-oil plant Oil, one ester of acetylated glycerol, acetylated diglycerides and their mixture.
The composition that item is 70. 16 is also surrounded by least one digestive ferment of coating, wherein the coating includes intestines Soluble polymer.
The composition that item is 71. 70, wherein the coating is also comprising at least one inorganic material.
The composition that item is 72. 71, wherein the enteric polymer and inorganic material are with about 4:1 to about 1:25 ratio In the presence of.
The composition that item is 73. 70, wherein the enteric polymer is selected from Cellacefate, adjacent benzene two Formic acid hydroxypropyl methyl cellulose, hydroxypropylmethylcellulose acetate succinate, poly- acetate phthalate vinyl acetate, methyl-prop Olefin(e) acid-methylmethacrylate copolymer and shellac.
The composition that item is 74. 71, wherein at least one inorganic material includes basifier.
The composition that item is 75. 74, wherein the basifier is selected from talcum, silica, sodium salt, calcium salt, magnesium salts, aluminium Salt, aluminium hydroxide, calcium hydroxide, magnesium hydroxide and their mixture.
The composition that item is 76. 70, wherein the coating also includes plasticizer.
The composition of 77. 76, wherein the plasticizer be selected from glyceryl triacetate, tributyl citrate, triethyl citrate, Acetoxyl group tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor-oil plant Oil, one ester of acetylated glycerol, acetylated diglycerides and their mixture.
The composition that item is 78. 32 is also surrounded by least one digestive ferment of coating, wherein the coating includes intestines Soluble polymer.
The composition that item is 79. 78, wherein the coating is also comprising at least one inorganic material.
The composition that item is 80. 79, wherein the enteric polymer and inorganic material are with about 4:1 to about 1:25 ratio In the presence of.
The composition that item is 81. 78, wherein the enteric polymer is selected from Cellacefate, adjacent benzene two Formic acid hydroxypropyl methyl cellulose, hydroxypropylmethylcellulose acetate succinate, poly- acetate phthalate vinyl acetate, methyl-prop Olefin(e) acid-methylmethacrylate copolymer and shellac.
The composition that item is 82. 79, wherein at least one inorganic material includes basifier.
The composition that item is 83. 82, wherein the basifier is selected from talcum, silica, sodium salt, calcium salt, magnesium salts, aluminium Salt, aluminium hydroxide, calcium hydroxide, magnesium hydroxide and their mixture.
The composition that item is 84. 78, wherein the enteric coating also includes plasticizer.
The composition of 85. 84, wherein the plasticizer be selected from glyceryl triacetate, tributyl citrate, triethyl citrate, Acetoxyl group tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor-oil plant Oil, one ester of acetylated glycerol, acetylated diglycerides and their mixture.
A kind of 86. dosage forms of item, tablet or capsule including the composition containing item 62.
The dosage form that item is 87. 86, wherein the dosage form is the capsule of the composition filled with item 62.
The dosage form that item is 88. 87, wherein the capsule has about 2% or smaller water content.
The dosage form that item is 89. 87, wherein the capsule is formed by being selected from following substance：Cellulosic polymer, hydroxypropyl Methylcellulose, starch, polysaccharide, pullulan and gelatin.
The dosage form that item is 90. 89, wherein the capsule includes hydroxypropyl methyl cellulose.
The dosage form that item is 91. 89, wherein the capsule has the water capacity less than about 4%.
The dosage form that item is 92. 89, wherein the capsule has the water capacity less than about 2%.
A kind of 93. packagings, it includes the sealing container being made of barrier material, drier and at least one item 47 Dosage form, wherein the drier and at least one dosage form are in the sealed container interior.
The packaging that item is 94. 93, wherein the barrier material is selected from metal, glass, plastics and the plastics coated with metal.
The packaging that item is 95. 93, wherein the drier is selected from molecular sieve, clay, silica gel, activated carbon and their group It closes.
The packaging that item is 96. 95, wherein the drier is molecular sieve.
A kind of 97. packagings, it includes the sealing container being made of barrier material, drier and at least one item 54 Dosage form, wherein the drier and at least one dosage form are in the sealed container interior.
The packaging that item is 98. 97, wherein the barrier material is selected from metal, glass, plastics and the plastics coated with metal.
The packaging that item is 99. 97, wherein the drier is selected from molecular sieve, clay, silica gel, activated carbon and their group It closes.
The packaging that item is 100. 99, wherein the drier is molecular sieve.
A kind of 101. packagings, it includes the sealing container made of barrier material, drier and at least one item 58 Dosage form, wherein the drier and at least one dosage form are in the sealed container interior.
The packaging that item is 102. 101, wherein the barrier material is selected from metal, glass, plastics and the modeling coated with metal Material.
The packaging that item is 103. 101, wherein the drier is selected from molecular sieve, clay, silica gel, activated carbon and their group It closes.
The packaging that item is 104. 103, wherein the drier is molecular sieve.
105. treat or prevent the methods with the digestion relevant illness of azymia, and the described method includes by the combination of item 1 Object gives the mammal of this needs.
106. treat or prevent the methods with the digestion relevant illness of azymia, and the described method includes by the combination of item 16 Object gives the mammal of this needs.
107. treat or prevent the methods with the digestion relevant illness of azymia, and the described method includes by the combination of item 32 Object gives the mammal of this needs.
108. treat or prevent the methods with the digestion relevant illness of azymia, and the described method includes by the combination of item 1 The drug of object and raising gastrointestinal tract pH give the mammal of this needs.
The method that item is 109. 108, wherein the drug is selected from proton pump inhibitor and antacids.
The method that item is 110. 108, wherein the administration includes giving the dosage form of the composition comprising item 1 and comprising raising Another dosage form of the drug of gastrointestinal tract pH.
The method that item is 111. 108, wherein the administration includes giving the composition comprising item 1 and improves gastrointestinal tract pH's The single formulation of drug.
The method of the composition of 112. preparations 63 of item, the described method includes：
It is about 3.6g water/m in water capacity3Or with including enteric polymer and at least one inorganic material in smaller atmosphere The coating of material is coated the particle of at least one digestive ferment, is consequently formed a variety of delayed release granules.
The method that item is 113. 112, wherein the atmosphere includes air, nitrogen or inert gas.
The method of 114. 112, wherein at least one inorganic material and the enteric polymer being dissolved in acetone Mixture is coated the particle of at least one digestive ferment.
The method of the composition of 115. preparations 71 of item, the described method includes：
It is about 3.6g water/m in water capacity3Or with including enteric polymer and at least one inorganic material in smaller atmosphere The coating of material is coated the particle of at least one digestive ferment, is consequently formed a variety of sustained release dosage units.
The method that item is 116. 115, wherein the atmosphere includes air, nitrogen or inert gas.
The method of 117. 115, wherein at least one inorganic material and the enteric polymer being dissolved in acetone Mixture is coated the particle of digestive ferment.
The method of the composition of 118. preparations 79 of item, the described method includes：
It is about 3.6g water/m in water capacity3Or with including enteric polymer and at least one inorganic material in smaller atmosphere The enteric coating of material is coated the particle of at least one digestive ferment, is consequently formed a variety of sustained release dosage units.
The method that item is 119. 118, wherein the atmosphere includes air, nitrogen or inert gas.
The method of 120. 118, wherein at least one inorganic material and the enteric polymer being dissolved in acetone Mixture is coated the particle of digestive ferment.
The method of the composition of 121. preparations 1 of item, the described method includes：
The digestive ferment is prepared, wherein the digestive ferment has about 3% or smaller water capacity.
The method of the composition of 122. preparations 16 of item, the described method includes：
The digestive ferment is prepared, wherein the digestive ferment has about 0.6 or smaller water activity.
The method of the composition of 123. preparations 32 of item, the described method includes：
The digestive ferment is prepared, is no more than wherein the digestive ferment is shown after the accelerated stability test of six months 15% digestive enzyme activity loss.
The composition that item is 124. 1,16 or 32, wherein at least one digestive ferment is pancreatic lipase.
The composition that item is 125. 124, wherein the pancreatic lipase is from pig.
126. a kind of dosage forms of item, wherein the dosage form is zero dosage form excessively filled of the composition comprising item 124.
127. methods for treating pancreatic exocrine insufficiency in patients, the described method includes by a effective amount of item 124 composition gives patient in need.
The method that item is 128. 127, wherein the patient suffers from cystic fibrosis.
The method that item is 129. 127, wherein the fat absorption that the treatment mitigates in the patient is bad.
The method that item is 130. 127, wherein the treatment increases the fat absorption coefficient in the patient.
The method that item is 131. 128, wherein the fat absorption coefficient in the treatment increase patient is at least about 85%。
The method that item is 132. 130, wherein the increase of fat absorption coefficient is in no co-administered in the patient Occur in the case of proton pump inhibitor.
Specific embodiment
One aspect of the present invention is related to stabilized digestive enzyme compositions.Term " stabilized digestive ferment " refers to The digestive ferment of basic enzymatic activity is maintained after long-term storage.Term " digestive ferment " refers to the enzyme in alimentary canal, and the enzyme decomposes food Object component so as to make food component by organism absorb or absorb.
Being suitable for the invention the nonrestrictive classification of digestive ferment includes lipase, amylase and protease.Digestive ferment Non-limiting examples include pancreatic lipase (also referred to as pancreatinum (pancreatin)), lipase (lipase), colipase (co-lipase), trypsase (trypsin), chymotrypsin (chymotrypsin), chymotrypsin B (chymotrypsin B), pancreas peptase (pancreatopeptidase), Carboxypeptidase A (carboxypeptidase A), protaminase (carboxypeptidase B), glycerol ester hydrolase (glycerolester hydrolase), phosphatidase (phospholipase), sterol ester hydrolase (sterol ester hydrolase), elastoser (elastase), swash Peptide protoenzyme (kininogenase), ribalgilase (ribonuclease), deoxyribonuclease (deoxyribonuclease), alpha-amylase (α-amylase), papain (papain), chymopapain (chymopapain), glutelin enzyme (glutenase), bromelain (bromelain), ficin (ficin), Beta amylase (β-amylase), cellulase (cellulase), beta galactosidase (β-Galactosidase), lactase (lactase), the mixture of invertase (sucrase), isomaltase (isomaltase) and these enzymes.
In one embodiment of the invention, the stabilized digestive ferment is pancreatin.Term used in this application " pancreatin (pancreatic enzyme) " refers to any enzyme type (such as amylase, fat present in pancreas secretion The mixture of enzyme, protease or these enzymes) or pancreas origin any extract (such as pancreatinum) with enzymatic activity.It is described Pancreatin can by from pancreas extract or manually prepare obtain or be never pancreas other sources (such as microorganism, plant or Other animal tissues) in obtain.
In another embodiment of the present invention, the stabilized digestive ferment is pancreatic lipase.Term " pancreas fat Enzyme " or " pancreatinum " refer to the mixture of several types enzyme, these enzymes include amylase, lipase and protease.Pancreas fat Enzyme can be for example from Nordmark Arzneimittel GmbH or Scientific Protein Laboratories LLC business It obtains.
In an embodiment of the present composition, the stabilized digestive ferment includes lipase.Term " fat Fat enzyme " refers to be catalyzed lipid hydrolysis for glycerine and the enzyme of simple fatty acids.
The example for being suitable for the invention lipase includes but not limited to animal tallow enzyme (such as pork fat enzyme), bacterium fat Fat enzyme (such as pseudomonas (Pseudomonas) lipase and/or bulkholderia cepasea category (Burkholderia) fat Enzyme), fungal lipase, plant fat enzyme, recombinant lipase (such as by recombinant DNA technology via suitable host cell (choosing From following any one：Bacterium, yeast, fungi, plant, insect or mammalian host cell) fat that generates in culture Fat enzyme, including the recombinant lipase with naturally occurring sequence homology or essentially identical amino acid sequence or by with naturally depositing Lipase homologous coding nucleic acid or essentially identical nucleic acid coding lipase etc.), through the lipase of chemical modification or this The mixture of a little enzymes.
In another embodiment of the present composition, the stabilized digestive ferment includes amylase.Term " amylase " refers to diastatic glycoside hydrolase (glycoside hydrolase enzyme), such as alpha-amylase, β- Amylase, gamma amylase, acid alpha-D-glucosidase (acid α-glucosidases), ptyalin (such as saliva element (ptyalin)) etc..
Include but not limited to animal amylase, bacterial amylase, amylomycin suitable for the amylase of the present composition Enzyme (such as aspergillus (Aspergillus) amylase, be preferably aspergillus oryzae (Aspergillus oryzae) amylase), plant Amylase, restructuring amylase (such as by recombinant DNA technology via suitable host cell (be selected from following any one：Carefully Bacterium, yeast, fungi, plant, insect or mammalian host cell) amylase that generates in culture, including with naturally depositing Sequence homology or essentially identical amino acid sequence restructuring amylase or by with naturally occurring amylase code nucleic acid Amylase of homologous or essentially identical nucleic acid coding etc.), the mixture through the amylase of chemical modification or these enzymes.
In another embodiment of the present composition, the stabilized digestive ferment includes protease.Term " protease " typically refers to make between the amino acid of protein enzyme that peptide bond is broken (such as protease (proteinase), peptide Enzyme (peptidase) or proteolytic enzyme (proteolytic enzyme)).Protease usually reflects according to its catalytic type It is fixed, such as aspartic peptidase, cysteine (sulfydryl) peptase (cysteine (thiol) peptidase), metallopeptidase, silk Propylhomoserin peptase, threonine peptase, alkalescence or semialkaline protease, neutral proteinase and the unknown peptase of catalytic mechanism.
Include serine protease, Soviet Union suitable for the non-limiting examples of the present composition or the protease of peroral dosage form Serine protease, cysteine proteinase, aspartic protease (such as plasmepins (plasmepsin)), metalloproteinases, hydroxyproline enzyme etc..In addition, suitable for the present composition or the egg of peroral dosage form White enzyme includes but not limited to animal protease, bacterialprotease, fungal proteinase (such as Aspergillus melleus albumen Enzyme), plant rennet, recombinant protease (such as by recombinant DNA technology via suitable host cell (selected from following any It is a kind of：Bacterium, yeast, fungi, plant, insect or mammalian host cell) protease that generates in culture, including with The recombinant protease of naturally occurring sequence homology or essentially identical amino acid sequence or by being compiled with naturally occurring protease Protease etc. of the homologous or essentially identical nucleic acid coding of code nucleic acid), the mixture of chemically modified protein enzyme or these enzymes.
The composition or peroral dosage form of the present invention can include one or more lipase (i.e. a kind of lipase or two kinds or more A variety of lipase), one or more amylase (i.e. a kind of amylase or two or more amylase), one or more albumen The mixing of enzyme (i.e. a kind of protease or two or more protease), one or more lipase and one or more amylase The mixture, one or more amylase and one or more eggs of object, one or more lipase and one or more protease The mixture of white enzyme or one or more lipase and one or more amylase and the mixture of one or more protease.
In one embodiment, the digestive ferment be pig pancreas extract (pancreatic extract), the pig Pancreas extract include various lipase (such as lipase, colipase, phospholipase A2, cholesterol esterase), protease (such as Trypsase, chymotrypsin, Carboxypeptidase A and B, elastoser, kininogenase, trypsin inhibitor), amylase and appoint The nuclease (ribalgilase, deoxyribonuclease) of choosing.In another embodiment, the digestive ferment substantially with people Pancreatic juice is similar.In another embodiment, the digestive ferment is United States Pharmacopeia pancreatic lipase (pancrelipase USP). In another embodiment, the digestive ferment is pancreatic lipase ESP, the lipase active with 69-120U USP/mg, big In or equal to the amylase activity of 216U USP/mg, the proteinase activity more than or equal to 264U USP/mg and it is more than or waits In the total protease activity of 264U USP/mg.
Lipase active in the composition or peroral dosage form of the present invention can be about 4500-25,000IU, for example, about 4500-5500IU, about 9000-11,000IU, about 13,500-16,500IU or about 18,000-22,000IU.The combination of the present invention Amylase activity in object or peroral dosage form can be about 8100-180,000IU, for example, about 8000-45,000IU, about 17, 000-90,000IU, about 26,000-135,000IU or about 35,000-180,000IU.The composition or peroral dosage form of the present invention In proteinase activity can be about 8000-134,000IU, for example, about 8000-34,000IU, 17,000-67,000IU, 26, 000-100,000IU or 35,000-134,000IU.In one embodiment, the scope of the lipase active is about 4500-5500IU, the scope of the amylase activity are about 8000-45, and the scope of 000IU and the proteinase activity is about 8000-34,000IU.In another embodiment, the scope of the lipase active is about 9000-11,000IU, the shallow lake The scope of powder enzymatic activity is about 17,000-90,000IU and the scope of the proteinase activity is about 17,000-67,000IU. In another embodiment, the scope of the lipase active is about 13,500-16,500IU, the model of the amylase activity It is about 26,000-135,000IU to enclose and the scope of the proteinase activity is about 26,000-100,000IU.In another reality It applies in scheme, the scope of the lipase active is about 18,000-22,000IU, and the scope of the amylase activity is about 35, The scope of 000-180,000IU and the proteinase activity is about 35,000-134,000IU.
Lipase in the composition or peroral dosage form of the present invention:Protease:The proportion of amylase can be about 1:10:10 To about 10:1:1 or about 1.0:1.0:0.15 (being based on enzymatic activity).Amylase/fat in the composition or peroral dosage form of the present invention The proportion of enzyme can be about 1.8-8.2, about for example, about 1.9-8.2 and 2.0-8.2.The composition or peroral dosage form of the present invention The proportion of middle protease/lipase can be about 1.8-6.2, about for example, about 1.9-6.1 and 2.0-6.1.
In another embodiment, the activity of lipase, protease and amylase can be those described in lower Table A Activity：
Table A
The total amount (by weight) of digestive ferment can be about 20-100%, 20- in the composition or peroral dosage form of the present invention 90%th, 20-80%, 20-70%, 20-60%, 20-50%, 20-40%, 20-30% or can be about 20%, about 30%, about 40%, about 50%th, about 60%, about 70%, about 80%, about 90% or about 100%.In one embodiment, the total amount of digestive ferment is 60-90%. In another embodiment, the total amount of digestive ferment (such as pancreatic lipase) is about 68-72%.
In one embodiment, the water capacity of the present composition or peroral dosage form comprising at least one digestive ferment is About 3% or smaller, about 2.5% or smaller, about 2% or smaller, about 1.5% or smaller or about 1% or smaller, be included in these numerical value it Between all scopes and sub-range (i.e. following any scope：About 2.5% to 3%, 2% to 3%, 1.5% to 3%, 1% to 3%, 2% to 2.5%th, 1.5% to 2.5%, 1% to 2.5%, 1.5% to 2%, 1% to 2%, 1% to 1.5% etc.).It has been found that maintain low contain The present composition or peroral dosage form of moisture and maintain conventional group of higher water capacity (such as on about 3% or higher) It closes object and compares and substantially relatively stablize.
Term " water capacity " also referred to as " water content (water content) ", refers to the water contained by composition.It is right In the case of change in water capacity for the immovable composition of volume, the water capacity can be based on volume (i.e. by volume) And it is expressed as the ratio of biodiversity and substance dry bulk.The composition of stereomutation in the case of for changing in water capacity For, the water capacity can be based on weight (i.e. by weight) and be expressed as and (water quality removed afterwards is dried)/(sample Unit dry mass).Water capacity determines to realize by any conventional method known in the art.For example, described contain Moisture can be determined by chemistry titration such as Carl Fischer titration (Karl Fischer titration), wherein in electrification It learns and dissolves sample in titration cell.Water from sample is consumed in electrochemical reaction, and terminal passes through potentiometric analysis (potentiometrically) measure, thus the direct measurement result in relation to water in sample is provided.Alternatively, may be used Using relatively simple thermogravimetry (thermogravimetric method) such as " loss on drying " (LoD), wherein by Sample quality is measured before and after draining dry (controlled drying).Dried mass loss is attributed to The loss of moisture.Commercially available moisture analyser (such as can be obtained from Mettler Toledo, Sartorius AG etc.) also can use In definite water capacity.The water capacity of the present composition or peroral dosage form can be by any appropriate method known in the art such as LoD is measured.
In another embodiment, the water activity of the present composition or peroral dosage form comprising at least one digestive ferment It is about 0.6 or smaller, about 0.5 or smaller, about 0.4 or smaller, about 0.3 or smaller, about 0.2 or smaller or about 0.1 or smaller, bag Include all scopes and sub-range (i.e. following any scope between these numerical value：About 0.5 to 0.6,0.4 to 0.6,0.3 to 0.6th, 0.2 to 0.6,0.1 to 0.6,0.4 to 0.5,0.3 to 0.5,0.2 to 0.5,0.1 to 0.5,0.3 to 0.4,0.2 to 0.4, 0.1 to 0.4,0.2 to 0.3,0.1 to 0.3,0.1 to 0.2 etc.).It has been found that maintain of the present invention group of low water activity It closes object or peroral dosage form is substantially relatively stablized compared with the conventional digestion enzymatic compositions for maintaining higher water activity level.
Water activity is the relative usability (relative availability) of water in substance also referred to as " aw ".This Shen The term " water activity " that please be used is defined as in sample the vapour pressure of water divided by pure water in mutually synthermal vapour pressure.Pure distillation Water has definite active for 1 water.Water activity is temperature dependency.In other words, water activity with temperature changes and changes.At this It is that about 0 DEG C to the about 50 DEG C temperature for being preferably from about 10 DEG C to about 40 DEG C measures water activity in scope in invention.
The water activity of product can be determined by measuring the relative humidity of sample surrounding air in balance.Therefore, to sample The measurement of water activity usually carries out in closed (typically isolating) space that this balance can occur in product.In balance, The relative humidity of the active and described air of the water of sample is equal, therefore in relation to the equilibrium relative humidity (ERH) of air in chamber (ERH) measurement result provides the measurement result in relation to sample water activity.At least two different types of water activity instruments are It is commercially available.A type of water activity instrument uses chilled-mirror type dew point technology (chilled-mirror dewpoint Technology) (such as can be from Decagon Devices, AquaLab that Inc. is obtainedTMWater activity meter), and other instrument Device (such as can be lived by changing resistance or changing the sensor of capacitance relative humidity is measured from water that Rotronic is obtained Property meter).The water activity of the present composition or peroral dosage form can be measured by any appropriate method known in the art.
In another embodiment, the present composition or oral agents of at least one stabilized digestive ferment are included Type loss of enzyme activity shown after the accelerated stability test of six months is no more than about 25%, is no more than about 20%, is no more than About 15%, it is no more than about 12%, no more than about 10%, no more than about 8% or no more than about 5%.
Term " accelerated stability test " or " accelerated storage test " refer to for simulating relatively long-term storage requirement pair The test method of the influence of enzymatic activity, the method can carry out within the relatively short time.Accelerated stability test method be Reliable replacement method as actual time stability test as is generally known in the art, and the storage of biological product can be predicted exactly Deposit the time limit.Such " accelerated stability test " condition is known in the art, and and International Conference for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use:Stability Testing of New Drug Substances and Products Q1A are consistent, are incorporated herein by reference in its entirety.
A kind of method of accelerated stability test is included in 40 DEG C/75% relative humidity and the sample of digestive enzyme compositions exists It is stored 6 months in Nialene (nylon, aluminium, polyethylene laminated object) (GOGLIO SpA, Milan) bag of sealing.
After storage (or during storage regularly), the routine for measuring digestive enzyme activity can be used in the enzymatic activity of sample Method tests (such as United States Pharmacopoeia, Pancrelipase:Assay for lipase Activity is incorporated herein by reference in its entirety).
The composition or peroral dosage form of the present invention also can further include one or more enhancings or improve present invention combination The stabilizer of object or peroral dosage form stability.The non-limiting examples of suitable stabilizer include proline (proline), seaweed Sugared (trehalose), glucan (dextran), maltose (maltose), sucrose (sucrose), mannitol (mannitol), Polyalcohol (polyol), silica gel (silica gel), aminoguanidine (aminoguanidine), Pyridoxamine (pyridoxamine), Anhydrous metal salt (anhydrous metal salt) is such as sodium acid carbonate, magnesia, calcium oxide, aluminium oxide and above-mentioned substance Mixture.The one or more stabilizer can have about 3% or smaller water capacity and/or 0.6 or smaller water activity.
Include seaweed available for the non-limiting examples of the present composition or the trehalose of the suitable form of peroral dosage form Sugared dihydrate (TD), amorphous trehalose (AT), anhydrous trehalose (such as anhydrous amorphous trehalose (AAT), anhydrous crystal Trehalose (ACT)).Powdered anhydrous trehalose can contain any AAT and/or ACT.Term " trehalose " used in this application is Refer to any physical form of trehalose, include the mixing of anhydrous form, partially hydrated form, fully hydrated form and these forms Object and their solution.Term " anhydrous trehalose " refers to any physical form of the trehalose containing less than 2% water.Seaweed The anhydrous form of sugar can contain 0-2% water.Amorphous trehalose contains about 2-9% water, and trehalose dihydrate closes object and contains about 9-10% Water.Anhydrous trehalose can be prepared as described in PCT/GB97/00367, be incorporated herein by reference in its entirety. In one embodiment, composition of the invention or peroral dosage form include one or more stabilized digestive ferments and anhydrous Trehalose.
The amount of anhydrous trehalose (AAT or ACT) can be about 5-50%, 5-40%, 5-30%, 5- in the composition of the present invention 20%th, 5-15%, 5-10% or 7-15% or be about 5%, about 7%, about 10%, about 15% or about 20%.
Anhydrous trehalose can be by the form composition incorporated in the present invention or peroral dosage form of powder.The anhydrous trehalose The granularity of powder can be in the range of about 2-2000 μm.
The present composition or peroral dosage form comprising one or more stabilized digestive ferments and anhydrous trehalose carry Improved enzyme stability is supplied.It is believed that anhydrous trehalose as follows obtains the composition of the present invention or peroral dosage form With stabilization：The anhydrous trehalose absorb or isolate moisture from ambient humidity from manufacturing process or preparation in itself in Residual moisture.
Desired use and needs based on the composition, the weight of the stabilized digestive ferment and the stabilizer Proportion is about 99:1 to 80:20.The stabilizer can be as follows in composition or peroral dosage form incorporated in the present invention：To at least A kind of stabilized digestive ferment carries out wet method blending or dry blending at least one stabilizer.In one embodiment, Dry blending is carried out to one or more stabilized digestive ferments and one or more stabilizers.In another embodiment In, wet method blending is carried out to one or more stabilized digestive ferments and one or more stabilizers.
In addition to the stabilized digestive ferment and/or stabilizer (one or more), composition or mouth of the invention Oral dosage form can also include one or more pharmaceutical excipients.Term " excipient " includes improving processability, stability, agreeable to the taste Property etc. and be added to other medicinal in the active component (one or more) (such as described stabilized digestive ferment) of composition Ingredient.The non-limiting examples of suitable excipient include medicinal adhesive, stabilizer, disintegrant, lubricant, glidant, dilute Release agent and their mixture etc..Pharmaceutical formulation arts personnel should be understood that specific excipient can be at described group It closes in object and plays multiple functions.Therefore, adhesive is such as also being used as diluent.The excipient can have about 3% or smaller Water capacity and/or about 0.6 or smaller water activity.
The non-limiting examples of suitable adhesive include starch, sugar (such as lactose), sugar alcohol (such as xylitol, sorb Sugar alcohol, maltitol), cellulose (such as microcrystalline cellulose), modified cellulose (such as hydroxypropyl cellulose, carboxymethyl cellulose Plain sodium), alginic acid, polyvinylpyrrolidone (povidone) and their mixture.The non-limiting examples of suitable disintegrant Including calcium monohydrogen phosphate (dibasic calcium phosphate), dicalcium phosphate dihydrate, calcium phosphate (tribasic Calcium phosphate), alginic acid, hydroxypropyl cellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, crosslinking carboxylic first Base sodium cellulosate, swellable ion exchange resin (swellable ion exchange resin), alginate (alginate), formaldehyde-casein (formaldehyde-casein), cellulose, cross-linked carboxymethyl cellulose sodium (croscarmellose sodium), Crospovidone (such as crosslinked polyvinylpyrrolidone), microcrystalline cellulose, carboxymethyl form sediment Powder sodium, sodium starch glycollate (sodium starch glycolate), starch (cornstarch, rice starch (rice )) and their mixture starch.The non-limiting examples of suitable lubricant include calcium stearate, magnesium stearate, stearyl Fumarate sodium (sodium stearyl fumarate), stearic acid, zinc stearate, talcum, wax,With their mixture.The non-limiting examples of suitable glidant include colloid dioxy SiClx, talcum and their mixture.The non-limiting examples of suitable diluent include mannitol, sucrose, anhydrous phosphoric acid hydrogen Calcium, calcium phosphate dibasic anhydrous dihydrate (anhydrous dibasic calcium phosphate dihydrate), phosphoric acid Calcium, cellulose, lactose, magnesium carbonate, microcrystalline cellulose and their mixture.The non-limiting examples of suitable stabilizer include Trehalose, proline, glucan, maltose, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and their mixing Object.
In one embodiment, the disintegrant for Crospovidone (such as POLYPLASDONE XL, POLYPLASDONE XL-10).In another embodiment, the disintegrant is cross-linked carboxymethyl cellulose sodium (such as AC- DI-SOL).In another embodiment, the disintegrant is sodium starch glycollate (such as EXPLOTAB, EXPLOTAB CV).In another embodiment, composition of the invention or peroral dosage form can include the combination of disintegrant, such as microcrystalline cellulose Element and the combination of sodium starch glycollate or the combination of cross-linked carboxymethyl cellulose sodium and Crospovidone.
The amount of disintegrant can be any one of following scope：About 0.1-30%, 1%-30%, 1%-25%, 1%-20%, 1%- 15%th, 1%-10%, 1%-5%, 5%-10%, 5%-15%, 5%-20%, 5%-25% or 5%-30%.In one embodiment, disintegrant Amount be about 2%-4%, about 2%-3% or about 2.5%.
The non-limiting examples of suitable diluent include microcrystalline cellulose, starch, calcium phosphate, lactose, sucrose, sweet dew Alcohol, D-sorbite and combination thereof.In one embodiment, the diluent is microcrystalline cellulose (such as Avicel). In another embodiment, the diluent is starch.In another embodiment, the diluent for lactose (such as Pharmatol).In another embodiment, composition of the invention or peroral dosage form can include the combination of diluent, such as micro- The combination of crystalline cellulose, starch and lactose.
The amount of diluent can be any one of following scope：About 0.1-99%, 1%-30%, 1%-25%, 1%-20%, 1%- 15%th, 1%-10%, 1%-5%, 5%-10%, 5%-15%, 5%-20%, 5%-25% or 5%-30%.In one embodiment, diluent Amount be about 2%-5%, 3%-5% or about 4%.
One or more excipient of the present composition or peroral dosage form can be used as that the composition is made further to stablize Drier.Can be used as the appropriate excipients of drier includes combining closely or reducing any medicinal of composition water activity with water Excipient.For example, the composition of the present invention can include about 1-4% silica gel or about 2.5% silica gel.
The composition of the present invention can be prepared into any suitable peroral dosage form.The non-limiting examples bag of suitable dosage form Include tablet, capsule or wafer (sachet).Because some digestive ferments such as pancreatic lipase may need protection that it is made to refer to 12 Stomach inactivation does not occur before enteric release, it is possible that it is desirable that, stabilized digestive enzyme compositions or peroral dosage form of the invention It is provided in the form of controlling delivery formulations or delayed release preparation.Such control delivery formulations or delayed release preparation can wrap Enteric-coated tablet or particle are included, the enteric coating inactivates for pH sensibility digestive ferments to be protected to make it that stomach not occur, and The digestive ferment is discharged in duodenum.Alternatively, the control delivery formulations may include filled with the present invention through steady Surely the digestive enzyme compositions or the capsule of peroral dosage form changed go out wherein the capsule protects content to make it that stomach not occur It is living, and the digestive ferment is discharged in duodenum.However, stabilized digestive enzyme compositions of the invention or peroral dosage form are not It is limited to the digestive ferment that stomach inactivation easily occurs, such as is some digestive ferments of natural stabilisation in gastric environment, such as gastric lipase, a system Row protease (those protease for including pancreas origin) and amylase.The some digestive ferments tool for obtaining or extracting from microorganism There is inherent stability or carried out chemical modification by being crosslinked.
When the composition of the present invention is prepared piece agent, methods known in the art can be used to described stabilized Digestive ferment (one or more) carries out " tabletting " (forming tablet), then reuses methods known in the art enteric coating It is coated.
When the composition of the present invention is configured to capsule, methods known in the art can be used to prepare the interior of capsule It is tolerant.For example, the stabilized digestive enzyme compositions can be come by the particle or the form of tablet suitably incorporated in capsule It provides.
Term " particle " used in this application is included on fine powder (fine powder) (having the grain size that scope is about 1 μm) To the piller (pellet) of a diameter of about 5mm.
Stabilized digestive enzyme compositions also can shape to be surrounded by the particle of coating, wherein the coating includes enteric solubility Polymer.Term " enteric polymer " refers to the polymer for protecting digestive ferment that it is made not contacted with gastric content, such as in acid Property pH when stablize but in higher pH quickly disintegrated polymer or such polymer, hydrolysis rate or erosion rate it is slow Enough to ensure when digestive ferment under one's belt when contact of the gastric content with digestive ferment be relatively small, this other portion with gastrointestinal tract Split-phase is anti-.The non-limiting examples of enteric polymer include those enteric polymers known in the art, it is such as modified or Unmodified natural polymer (such as Cellacefate (cellulose acetate phthalate), adjacent benzene two Formic acid hydroxypropyl methyl cellulose (hydroxypropyl methylcellulose phthalate), acetate succinate hydroxypropyl Ylmethyl cellulose (hydroxypropylmethylcellulose acetate succinate) and shellac) or synthesize poly- Close object (such as acrylic acid (ester) polymer or copolymer, methacrylate polymer and copolymer, methylmethacrylate copolymer With methacrylic acid/methylmethacrylate copolymer).
Enteric polymer coating can be the polymer of synthesis, and the polymer optionally includes inorganic material such as basifier (alkalinizing agent).Obtained coated granule provides sustained release pearl, and the pearl is included containing stabilized Digestive ferment (one or more) core and wrap up the enteric coating of the core.It then can be by coated stabilisation digestive ferment Particle formulation piece agent or capsule.
The enteric polymer and at least one inorganic material provide enteric properties for the coating of the present invention.Change speech It, when as drug, the coating will protect drug that it is made not contacted with stomach acidity environment as barrier, and in drug The release of drug is substantially prevented before arrival small intestine (i.e. the release of enzyme under one's belt is less than the about 10-20% of enzyme total amount in composition).
The inorganic material may include such as basifier.The non-limiting examples of basifier include silica, sodium salt, calcium Salt, magnesium salts, aluminium salt, aluminium hydroxide, calcium hydroxide, magnesium hydroxide, talcum and combination thereof.In one embodiment, institute Basifier is stated as talcum.
Based on the desired use of the composition, the proportion of the enteric polymer and at least one inorganic material It can be about 10 by weight:1 to about 1:60.In another embodiment, the enteric polymer and at least one are inorganic The proportion of material by weight about 8:1 to about 1:50.In another embodiment, the enteric polymer and extremely A kind of few proportion of inorganic material by weight about 6:1 to about 1:40.In another embodiment, the enteric solubility Polymer and the proportion of at least one inorganic material by weight about 5:1 to about 1:30.In another embodiment, The proportion of the enteric polymer and at least one inorganic material by weight about 4:1 to about 1:25.At another In embodiment, the proportion by weight about 4 of the enteric polymer and at least one inorganic material:1 to about 1: 9.In another embodiment, the proportion of the enteric polymer and at least one inorganic material is by weight about 10:4 to about 10:7.
In one embodiment, composition of the invention or peroral dosage form include enteric-coated stabilisation digestive ferment Particle, the enteric coating include enteric polymer and inorganic material (such as talcum).In specific embodiments, the enteric The inorganic material of clothing accounts for the about 1-10% weight of the particle total weight by weight.In another embodiment, it is described inorganic Material accounts for about 3%, about 5%, about 7% or about the 10% of the particle by weight.In other embodiments, the inorganic material is Basifier, and account for the about 20-60% of dry coating (dry coating) weight.In other embodiments, the basifier is About 25%, about 30%, about 35%, about 40%, about 45%, about 50% or about the 55% of dry coat weight (is included in the institute between these numerical value There are scope, sub-range and value).In specific embodiments, the basifier is talcum.In another specific embodiment In, the dry coating of the particle includes about 35% talcum.
In another embodiment of the present invention, the coating also includes plasticizer.The example bag of suitable plasticizer It includes but is not limited to glyceryl triacetate (triacetin), tributyl citrate, triethyl citrate, acetoxyl group tri-n-butyl citrate (acetyl tri-n-butyl citrate), diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, Castor oil, one ester of acetylated glycerol (acetylated mono-glyceride), acetylated diglycerides (acetylated ) and their mixture di-glyceride.
The dosage form of the present invention can be that (such as the digestive enzyme compositions that stabilize are surrounded by enteric containing the present composition Property polymer and basifier control release particle) capsule.Capsule in itself can be by any standard biologic known in the art Degradation material is formed, the biodegradable material such as gelatin, polysaccharide (such as pullulan (pullulan)) or modified Cellulosic material (such as hydroxypropyl methyl cellulose).In order to improve the stability of the stabilized digestive ferment, can fill out The capsule being made of low water capacity material is dried or may be selected before filling to capsule.In an embodiment party of dosage form of the present invention In case, the capsule is made of hydroxypropyl methyl cellulose.In another embodiment of dosage form of the present invention, the capsule by Following hydroxypropyl methyl cellulose is formed, and the water content of the hydroxypropyl methyl cellulose is about 6% or smaller, such as is appointed below What is a kind of：About 4% or smaller, about 2% or smaller, about 2-6% or about 4-6%.In another embodiment, the capsule is by aqueous Hydroxypropyl methyl cellulose of the amount less than about 2% is formed.
The dosage form of the present invention can include the mixture of single digestive ferment or digestive ferment.If by stabilized digestive ferment group It closes object and is configured to enteric-coated particle, then the coated particle, which can each contain, includes single digestive ferment or digestive ferment The core of mixture.The dosage form can also include coated particle, and each particle nominally has identical composition or institute The mixture of variety classes coated granule can be included by stating dosage form.For example, the dosage form can be the capsule filled with coated granule, Wherein each coated granule has the core comprising pancreatic lipase.Alternatively, the dosage form can be filled with coated granule Capsule, some of coated granules have the core comprising pancreatic lipase, and other coated granules have include different fat The core of fat enzyme or protease or amylase.Any appropriate combination of the coated granule of difference composition can be used in desired by offer Therapeutic effect.
In addition, when the dosage form of the present invention is made of the coated granule of stabilized digestive ferment, each particle can be respective It may include the mixture of particle with identical coating composition or the dosage form, some in these particles are with different bags Clothing forms.Any appropriate combination of coating composition can be used in providing control release or the therapeutic effect of desired type.
The core of coated granule can have any suitable granularity or shape.For example, the coated particle can be in grain Spend the form for the coating powder that scope is about 50-5000 microns or the " small pieces that can be about 2-5mm in nominal particle size range (minitab) " form.For other application, the core of coated granule can be that nominal particle size is less than about 2mm for example, about 1- " microplate (microtab) " of 2mm.
In one embodiment, composition of the invention or peroral dosage form can include a variety of coated digestive ferment (examples Such as pancreatic lipase) particle.It is polymer-bonded that the digestion enzyme granulate can include digestive ferment, at least one disintegrant, at least one Agent or diluent and optionally at least one plasticizer, optionally at least one glidant and optionally at least one lubrication Agent.In one embodiment, the digestion enzyme granulate can include about at least one disintegration of the digestive ferment of 60-90%, about 1-4% At least one polymer adhesive or diluent of agent, about 2-6% and optionally at least one plasticizer of about 0.5-1.0% are appointed Select at least one glidant of about 0.2-0.6% and at least one lubricant of optional about 0.2-0.6%.For example, the digestive ferment Particle can include about the pancreatic lipase of 60-90%, cross-linked carboxymethyl cellulose sodium of about 1-4%, about 0.5-1.0% rilanit special, The magnesium stearate of the microcrystalline cellulose of the colloidal silicon dioxide of about 0.2-0.6%, about 2-6% and about 0.2-0.6%.The coating Can include at least one enteric polymer, about 4-10% at least one basifier (total weight based on particle) and optionally At least one plasticizer.In one embodiment, it is described be coated can include about 10-20% at least one enteric polymer, At least one basifier of about 4-10% and at least one plasticizer of about 1-2% (total weight based on particle).It is for example, described Coating can include about the lemon of the Hydroxypropyl Methylcellulose Phathalate of 10-20%, the talcum of about 4-10% and about 1-2% Triethylenetetraminehexaacetic acid ester (total weight based on particle).Then, a variety of coated digestion enzyme granulates can shape as tablet or be filled into glue In capsule.In one embodiment, the capsule includes hydroxypropyl methyl cellulose.
Compared with conventional digestive ferment (such as pancreatic lipase) composition and dosage form, composition of the invention and this hair is included The dosage form of bright composition has improved stability.Therefore, the digestive ferment that clinic has dosage is just delivered to the trouble of this needs For person, dosage form of the invention need not " excessive filling " (the i.e. zero excessive filling) as conventional digestive ferment dosage form.It is conventional Digestive enzyme compositions and dosage form up to 65% excessive fill level (the 165% of digestion enzyme dosage needed for i.e.) is needed to compensate difference Enzyme stability.Therefore, there is uncertainty for the dosage that conventional digestive enzyme compositions are delivered.Therefore, it is conventional " excessive filling " dosage form after fabrication soon can transmissibility be higher than the digestive ferment of desired amount, but as time go by, enzymatic activity It may be down under desired dosage.
In one embodiment, the dosage form comprising the present composition substantially zero is excessively filled.Term is " basic Upper zero excessive filling " refers to such present composition, wherein the amount of additional digestive enzyme activity is (i.e. higher than projected dose The amount of additional enzymatic activity) less than or equal to about 10% (i.e. about 10%), less than about 10%, less than or equal to about 9%, be less than or equal to About 8%, less than or equal to about 7%, less than or equal to about 6%, less than or equal to about 5%, less than or equal to about 4%, less than or equal to about 3%th, less than or equal to about 2%, less than or equal to about 1% or about 0%.Thus, for example if desired dosage is about 4500IU fat Enzyme, the then dosage form that the present invention substantially zero excessively fills can contain and (be less than or equal to less than or equal to about 4950IU lipase 110% 4500IU lipase).In another embodiment, described zero dosage form excessively filled contains 4500IU lipase.
The composition or dosage form (such as tablet or capsule) of the present invention can be stored in any suitable packaging.For example, The packaging can be the glass for being threaded closure member or press-fit closure member (threaded or press-fit closure) Bottle or plastic bottle.Alternatively, composition of the invention or dosage form can be packaged as at " blister package (blister pack) " In unit dosage forms.Applicant have found that the improvement stability of the digestive enzyme compositions or dosage form can be moisture-proof by providing (moisture-proof) sealing element and/or damp-prrof packing provide.The non-limiting examples of suitable damp-prrof packing include glass Glass bottle, the plastic bottle for being associated with moisture barrier resin or coating, aluminised plastic (such as Mylar) packaging etc..Term " moisture-proof " is Refer to water permeability (permeability to water) and be less than about 0.5mg water/cm3The packaging in container volume/year.
Container (such as bottle) especially can make moisture enter closing for minimum with any suitable closure member during storage Component is closed.For example, the present invention composition or dosage form can with as Saf-Cap III-A (Van Blarcom Closures, Inc. closure member as) is closed, and the Saf-Cap III-A are included and are printed to liner (sealing liner) HS035Heat Seal/20F(SANCAP Liner Technology,Inc.)。
It, can be in the combination of the distribution present invention in order to ensure package integrity properties during storage and moisture be made to enter minimum Object or dosage form and after packing, to packing carry out leak check comprising the present composition or dosage form.For example, institute It states and packs and can examine as follows：Controlled vacuum state is applied to the closure member, and detects vacuum state with the time Past reduction.Suitable leak check equipment includes those equipment (such as LF-01-PKV types manufactured by Bonfiglioli Or PKV516 types).
Packaging comprising the present composition or dosage form also (is inhaled containing the drier that can reduce package interior humidity Substance, the substance with the substance of water reaction or absorption (adsorb) water for receiving (absorb) water), such as can be packed from being sealed in The dryer capsule of " removing " moisture in interior atmosphere.The non-limiting examples of the suitable desiccant of the package interior can be placed in Including zeolite (zeolite), (such as molecular sieve is such asMolecular sieve), clay (clay) (such as montmorillonite (montmorillonite clay)), silica gel, activated carbon or combination thereof.In one embodiment, the desiccant pack Containing molecular sieve.
In addition, common practice is, when packing oral drugs unit dose, by by fibrous material as cotton is formed " plug (plug) " is added to container top with the white space at the top of filling container, thus makes the mobile minimum of content.Fiber Property material is somewhat hygroscopic, and can be as " storage " of package interior moisture.Therefore, the implementation packed in the present invention In scheme, fibroid " plug " or cotton " plug " are not present in packaging.It is described in another embodiment packed in the present invention Packaging lack fibroid plug or cotton plug and comprising drier.
Routine techniques can be used to prepare in the composition of the present invention, but can illustrate to be modified to provide according to the application About 3% or smaller water capacity provides about 0.6 or smaller water activity or provides aobvious after trimestral accelerated stability test The stabilisation digestive enzyme compositions of no more than about 15% loss of activity are shown.For example, the particle of digestive ferment (such as pancreatic lipase) It can be coated in the fluidized bed coating equipment equipped with dehumidifier (dehumidifier).In one embodiment, the coating Device operates in the atmosphere with following water content：About 4g/m3Or smaller, about 3.5g/m3Or smaller, about 3g/m3Or smaller, About 2.5g/m3Or smaller, about 2.0g/m3Or smaller, about 1.5g/m3Or smaller, about 1.0g/m3Or smaller or about 0.5g/m3Or more All scopes and sub-range small, be included between these numerical value.The atmosphere being coated wherein may include the sky through dehumidifying Gas, the nitrogen through dehumidifying or another inert gas through dehumidifying.
The coating can by enteric polymer (and optional suspension inorganic material) in organic solvent solution Form is applied, the organic solvent such as alcohol (such as ethyl alcohol), ketone (such as acetone), dichloromethane or their mixture (example Such as the mixture of acetone/ethanol).
The composition of the present invention with provided in the patient of the relevant disease of digestion azymia or illness to fat, The improvement of protein and carbohydrate absorbs.In one embodiment, composition of the invention, particularly pancreatic lipase or Pancreatinum composition, available for treatment and the relevant pancreatic exocrine insufficiency of various diseases (EPI).The disease includes But it is not limited to cystic fibrosis (CF).In some embodiments, the composition can be in cystic fibrosis patient and other trouble It is substantially mitigated in person's (including pediatric patients) and the relevant malabsorptions of EPI (such as fat absorption is bad).In some implementations In scheme, the composition can be in cystic fibrosis patient by fat absorption coefficient (coefficient of fat Absorption, CFA) it is increased at least about 85% or bigger.When with other medicines or composition co-administered, it can be achieved that this A bit as a result, or, it can be achieved that these results in the case of not with other medicines co-administered.In one embodiment, not With proton pump inhibitor such asIn the case of waiting co-administereds, these CFA results are realized.
For being accredited as having low GI pH horizontal (gastrointestinal tract pH is horizontal), (such as GI pH are horizontal<About 4) patient and Speech, can be by by the composition of the present invention or dosage form and proton pump inhibitor, the antacids and other medicines for improving gastrointestinal tract pH Improvedd result is administered together.For example, the present invention composition or dosage form can with proton pump inhibitor, antacids or its Its drug is separately administered and (is administered prior to, concurrently with, or after administration proton pump inhibitor, antacids etc.).Alternatively, institute It can be single formulation with the pancreatinum combination of compositions of the present invention to state proton pump inhibitor, antacids or other medicines.
In another embodiment, the present invention provides the sides treated or prevented with the digestion relevant illness of azymia Method, the described method includes the mammals that the composition of the present invention is given to this needs.In one embodiment, the food in one's mouth Newborn animal is the mankind.
In another embodiment, the present invention provides the sides treated or prevented with the digestion relevant illness of azymia Method, the described method includes the mammal that the composition of the present invention or dosage form are given to this needs, wherein the combination of the present invention Object or dosage form also include the other medicines of proton pump inhibitor, antacids or increase GI pH in addition at least one digestive ferment. In another embodiment, the present invention provides the method treated or prevented with the digestion relevant illness of azymia, the methods Including administration composition of the invention or dosage form and include proton pump inhibitor, antacids or the other medicines for increasing GI pH Dosage form.
It can include wherein patient with the illness that the composition or dosage form of the present invention are treated without digestive ferment or low-level to disappear Change the illness of enzyme or wherein patient needs the disease of digestive ferment supplement administration (digestive enzyme supplementation) Disease.For example, the illness may include cystic fibrosis, chronic pancreatitis, other pancreatic diseases (such as hereditary pancreatitis, wound Pancreatitis and allograft pancreatitis (allograft pancreatitis), hemochromatosis after wound (hemochromatosis), Schwachman syndrome (Shwachman syndrome), liposis (lipomatosis) Or hyperparathyroidism (hyperparathyroidism)), the side effect of cancer or treatment of cancer, operation (such as stomach and intestine By-pass operation (gastrointestinal bypass surgery), Hewlett-Packard's that measure (Whipple procedure), full pancreas Resection (total pancreatectomy) etc.) side effect, wherein pancreatin cannot reach other illnesss, insufficient mixed of intestines Conjunction (poor mixing) (such as than rood II formulas gastrectomy (Billroth II gastrectomy), other types of stomach By-pass operation, gastrinoma (gastrinoma) etc.), drug therapy is (such as with melbine or for treating HIV symptoms and itself The treatment that the drugs of immunity disease such as diabetes carries out, pancreas can suffer from damaging in these diseases) side effect, obstruction (such as ductus pancreaticus and calculus of bile duct disease, pancreas and Tumors of Duodenum (pancreatic and duodenal neoplasm), pipe Narrow (ductal stenosis)), with the relevant malabsorption of chylous diarrhea (celiac disease), food allergy and Aging.
The amount that mammal (such as mankind) is given once daily in the composition or dosage form of the present invention depends on desired result. Technical staff the diagnosis of illness to be treated can be issued according to him needed for dosage prescription.
For example, for the treatment digestion azymia (such as with the relevant digestion azymia of cystic fibrosis) in the mankind and Speech, according to the recommendation of US FDA (U.S.'s food and Drug Administration), starting dose should be 500 to 1000 lipase lists Position/kg/ eats, and accumulated dose is no more than 2500 lipase units/kg/ meal or 4000 lipase units/g fat/meal.Typically, Patient should receive at least 4 dosage forms daily, be preferably administered together with food.
Embodiment
Embodiment 1
Pancreatic lipase MT (small pieces) is the blend of pancreatic lipase raw material (such as derived from Nordmark) and excipient, is used Circular 2mm diameters oblique impact head (beveled punch) carries out tabletting to it.Physical properties of the pancreatic lipase MT before coating is such as Shown in the following table 1.
* USP methods
Using the fluid bed Glatt-GPCG1 devices equipped with Munters ML1350 dehumidifiers in processing air-flow (process Airflow pancreatic lipase MT is coated with coated formula (table 2) in).With the processing air of three kinds of different water capacities (table 3) (process air) processes to be coated.For every batch of, coat weight is about the 15% of coated granule total weight.For The composition of the coated granule of each group processing conditions is (table 4) being substantially the same, and seem to be after microexamination it is homogeneous, It is smooth and homogeneous.
Three groups of samples (i.e. P9A165, P9A167 and P9A170) show residual corresponding with processing air-flow water capacity containing wet It measures (table 5).
The influence of loss of the residual moisture to activity over time is evaluated under the conditions of following accelerated stability：
Hard gelatin capsule (dosage 20,000IU lipase) is filled with above-mentioned three batches coated pancreatic lipase MT small pieces, And it is stored in 40 DEG C and 75% relative humidity in the Nialene bags of sealing.
Lipase active is evaluated after storing 15 days and 4 months.The results are shown in table 6.
Table 6 the results show that water capacity provides improved stability less than about 2% composition.Alternatively, exist Water capacity is less than 3.6g/m3To 0.4g/m3Atmosphere under be coated, thus provide improved stability.
Embodiment 2
Pancreatic lipase MT particles are coated (table 7) with two kinds of coated compositions containing not same amount talcum.
In order to ensure processing air-flow is in low water capacity (i.e. less than 1g/m3), it dehumidifies using equipped with Munters ML1350 The fluid bed Glatt-GPCG1 devices of device test (coating trial) to be coated.Coat weight is about 15%.Two batches Theory composition is referring to table 8.Microexamination shows that the coating on all samples is all smooth and homogeneous.Residual water capacity is led to Loss on drying is crossed to measure (table 9).
The influence of loss of the different coated compositions to activity over time carries out under the conditions of following accelerated stability Evaluation：
Hard gelatin capsule (dosage 20,000IU lipase) is filled with the coated pancreatic lipase MT of above-mentioned two batches, then It is stored in 40 DEG C and 75% relative humidity in the Nialene bags of sealing.
Lipase active is checked after storage 1,2 and 3 months, and the results are shown in table 10.
The results show that after being stored three months under the conditions of accelerated stability, for being coated with the coating of high talc content Sample (batch P9A240) for, loss of activity is significantly lower.Therefore, talc concentration is increased to about from about 1% 7%, this causes significantly improving for enzyme stability.
Embodiment 3
The effect of coated composition solvent is evaluated as follows：Prepare " high talcum " bag similar to those compositions described in table 7 Clothing composition and " low talcum " coated composition, unlike ethyl alcohol (96% ethyl alcohol, 4% water)/acetone solvent with 100% acetone generation For (table 11).
In order to ensure processing air-flow is in low water capacity (less than 1g/m3), using equipped with Munters ML1350 dehumidifiers Fluid bed Glatt-GPCG1 devices come be coated experiment.Coat weight is about 15%.The theoretical composition of two batches is referring to table 12.
Batch P9A318 is consistent with commercial product specification, but batch P9A352 tests (gastro- not over resistance to stomach resistance test).Microexamination shows, the film coating of the batch P9A352 light not as good as other coated samples It is sliding and homogeneous, this may be because compared with the ethanol/acetone mixture used in preceding sample acetone evaporation rate compared with Talc concentration in height and coating is higher.
Then batch P9A318 is evaluated as follows under the conditions of accelerated stability：
Hard gelatin capsule (dosage 20,000IU lipase) is prepared, and is stored in 40 DEG C and 75% relative humidity close In the Nialene bags of envelope.Lipase active is measured after storage 1,2 and 3 months, the results are shown in table 13.
Compared with the stability of the batch P9A230 prepared under similar coating conditions with similar coating, batch P9A318's Stability significantly improves (table 14).Therefore, 96% ethyl alcohol is replaced with acetone in coated preparation, this seems to provide at any time Elapse significantly lower loss of enzyme activity.
Embodiment 4
By CPS gelatine capsules and the identical coated lipase compositions of HPMC (hydroxypropyl methyl cellulose) capsules Filling.The water content of gelatine capsule is about 14%, and the water content of HPMC capsules is about 4%.In addition, one group of HPMC capsule is dried It is less than 2% to moisture level.All samples is made to receive accelerated stability condition (40 DEG C and 75% relative humidity;Sample is heated seal In Nialene bags), and tested lipase active after 15,30 and 90 days.The results are shown in the following table 15-17.
1) HPMC CPS (HPMC capsules) are to gelatin CPS (gelatine capsule)
As shown in table 15-17, the lipase compositions in HPMC capsules show under the conditions of accelerated stability storage 15, Significantly higher lipase active and compared with containing those of equilibrium moisture level HPMC capsules after 30 and 90 days, it is dry HPMC capsules provide preferable stability.
Embodiment 5
Gelatine capsule and hydroxypropyl methylcellulose capsules are filled with coated lipase compositions mini-tablet form.For The coating of gelatine capsule composition (P200050) contains about 10% talcum, and is used for hydroxypropyl methylcellulose capsules composition (P200550) coating contains about 33% talcum.Coated composition is identical in other aspects.The following table 18 is in acceleration for stabilization Property under the conditions of store after Degradation Level and the water capacity of composition compare.As shown in table 18, in the composition, Higher lipase activity level is related to relatively low moisture level.In addition, the composition being filled in HPMC capsules is than filling Composition in gelatine capsule is more stable.
Table 18
Embodiment 6
The effect of the storage capsule containing lipase compositions is evaluated as follows in the packaging comprising drier：Accelerating surely Qualitative condition (40 DEG C and 75% relative humidity;By sample heat seal in Nialene bags) under store 30 and 90 days after measure sample In lipase active.As shown in table 19 and 20, in the packaging comprising drier and in the item less than its equilibrium moisture content Lipase active is significantly higher in dry capsule under part.
2) drier
Drier 1：Silica gel existsIn bag
Drier 2：Molecular sieve existsIn bag
Embodiment 7
Using the mixture of acetone or alcohol/acetone as coating solvent, two kinds of coated compositions of pancreatic lipase MT particles Object is coated, and the coated composition has horizontal between " low " horizontal and " height " horizontal intermediate talcum used above (HP55:TEC:Talcum=10:1:5).The theoretical composition of two kinds of coating suspensions is shown in the following table 21.
In order to ensure processing air-flow is in low water capacity (less than 1g/m3), using equipped with Munters ML1350 dehumidifiers Fluid bed Glatt-GPCG1 devices come be coated experiment.
Each batch of following preparation：Pancreatic lipase MT is coated in the case where coat weight is about 15%.Three batches are used second Prepared by alcohol/acetone coating solvent, and three batches are prepared with acetone coating solvent.(the theoretical composition of six batches is phase to theory composition With) be shown in the following table 22.
Microexamination is carried out to the coating of all six kinds of samples, seems to be smooth and homogeneous.It then will be coated The particles filled capsules to HPMC of pancreatic lipase MT in, and be packaged in the vial containing drier (molecular sieve).Then will Bottle sealing, stores under the conditions of accelerated stability, and as shown in table 23 below lipase active is evaluated in day part.
The terms of packing of various samples is as follows.Using 12 HPMC capsules (dosage is 20,000IU lipase) and as dry The 1g molecular sieves (Minipax sorbent-Multisorb) of drying prescription are placed in the vial that capacity is 30mL.Bottle is with including print The Saf-CapIII-A closings of the HS035Heat Seal/20F of liner are made as, and are stored in 40 DEG C/75%RH.
As shown in table 23, the three kinds of samples prepared with ethanol/acetone coating solvent show that similar lipase active damages It loses.After storage 2 months, two kinds in the sample prepared with acetone coating solvent do not show any loss of activity, and the 3rd Kind shows 4% activity reduction.It is prepared by this sample ratio ethanol/acetone coating solvent for showing to be prepared with acetone coating solvent Sample it is more stable.
Embodiment 8
Microplate
In order to provide the further selection in relation to dosage, the significantly reduced preparation of tablet sizes is prepared for.Pancreatic lipase is total to The punch tabletting of mixed object circle 1.5mm diameters and 1.2mm radius of curvature.
Pressing parameter is set to obtain the microplate (" μ T ") that friability is less than 2.5% (USP methods).The property of batch P9A402 Matter is shown in Table 24.
In order to ensure processing air-flow is in low water capacity (less than 1g/m3), equipped with Munters ML1350 dehumidifiers Batch P9A402 is coated with the suspension with composition shown in table 2 in fluid bed Glatt-GPCG1 devices.Obtain 22% Coat weight.It is all smooth and homogeneous to show that all samples seem to the microexamination that film coating carries out.
The theoretical composition of batch P9A422 is shown in Table 25.
The microplate of other two batch is prepared as described above, and their property is shown in the following table 26.
Using the mixture of acetone or alcohol/acetone as coating solvent, pancreatic lipase microplate is in two kinds of suspensions One kind is coated, and the suspension has between above-mentioned " height " horizontal and " low " horizontal intermediate talcum level (HP55:TEC: Talcum=10:1:5) (table 27).
In order to ensure processing air-flow is in low water capacity (less than 1g/m3), using equipped with Munters ML1350 dehumidifiers Fluid bed Glatt-GPCG1 devices come carry out six times experiment.Coat weight is about 22%, and microexamination show it is described Coating is smooth and homogeneous.
The theoretical composition of each batch is summarized in table 28.
HPMC capsules are filled with above-mentioned coated microplate, and are packaged in the vial containing drier (molecular sieve). Bottle is closed with the Saf-Cap III-A comprising the HS035Heat Seal/20F for being printed to liner, and in accelerated stability It is stored under condition (40 DEG C and 75% relative humidity).Using 12 HPMC capsules (dosage is 5,000IU lipase) and as drying The 1g molecular sieves (Minipax sorbent-Multisorb) of agent are placed in the vial that capacity is 30mL.Such as 29 and 30 institute of table Show, in 20,30,40 and 60 days measurement lipase actives of storage.
All three samples prepared using ethanol/acetone coating solvent show similar behavior, and store two After month, lipase active loss is 2%-4%.Storage after two months, uses the activity of two kinds of samples prepared by acetone coating solvent Loss does not show any sign of lipase active loss, and the third sample shows that 5% lipase active reduces. Therefore, more more stable than the sample prepared with ethanol/acetone coating solvent by the use of acetone as composition prepared by coating solvent, this can It can be related to the water content of ethyl alcohol used.
The microplate of above-mentioned preparation is slightly rectangular (referring to table 24 and 26)；Ratio between microplate thickness and diameter is 1.22:1 to 1.15:1.
In order to further reduce the size of microplate, thickness and diameter proportion are prepared for close to 1:1 new sample (batch Q9A006), it is shown in table 31.
Batch Q9A006 is coated with 22% coat weight with the composition shown in table 32.In order to ensure processing gas Stream (is less than 1g/m in low water capacity3), use the fluid bed Glatt-GPCG1 devices equipped with Munters ML1350 dehumidifiers To be coated experiment.
The theoretical composition of coated microplate batch Q9A019 is identical with shown in table 28.Microexamination shows the coating It is smooth and homogeneous.
Above-described embodiment shows that the digestive enzyme compositions that stability is improved can be prepared as follows：Such as by using acetone Instead of hydrous ethanol/acetone coating solvent, in the processing air-flow through dehumidifying, (it is for example with 0.4g/m3To 3.6g/m3Containing wet Amount) in small pieces and microplate are coated, low water capacity and low water activity are thus maintained in the component of the composition.This Outside, level (such as the HP55 of inorganic material in coating is improved:TEC:Talcum proportion is 10:1:1 to 10:1:5), selection is inhaled Moist smaller capsule material (such as HPMC or HPMC of drying) and improve packing technique and (such as be stored in containing drying In the vial of the good seal of agent), these measures provide digestive enzyme compositions and the dosage form that stability is improved.
Embodiment 9
The following table 33 shows the acceleration for stabilization carried out to the pancreatic lipase small pieces being coated with Eudragit (acrylic resin) Property experiment (in bottle;40 DEG C and 75% relative humidity).
Table 33
The result shows that conventional enteric coating (such as Eudragit) cannot provide stabilized pancreatic lipase composition.
Embodiment 10
The implementation of dosage form is illustrated in the following table 34, and the dosage form includes various dosage/capsules as described in the previous embodiments The ER coating pearls being coated like that.
Embodiment 11
The following table 35 shows the water content of the container of all size containing the capsule comprising the present composition.It is described to contain Water includes whole water from capsule and penetrates into the water in container by 2 years periods of storage." equivalent molecular sieve (equivalent molecular sieves weight) " is the minimum for absorbing the molecular sieve needed for water present in container Amount.
Table 35
Embodiment 12
The research of III phase randomized double-blinds placebo controlled crossovers is carried out, so as to be 7 years old or bigger at the age with EPI In 34 CF patients to the therapeutic effect of the pancreatic lipase composition of table 34 compared with the therapeutic effect of placebo.Research exists It is carried out throughout 14 CF centers in the U.S..The Primary endpoint (primary endpoint) of research is compared to 5,000,10, 000th, 15,000 or 20,000 lipase units/capsule be combined in the case of to be less than or equal to 10,000 lipase lists Fat absorption coefficient and oral medication placebo after the daily dose oral medication pancreatic lipase composition of position/kg body weight Fat absorption coefficient afterwards.The secondary endpoints (secondary endpoint) of experiment have rated to determine protein adsorption The variation of nitrogen absorption coefficient and the variation of cholesterol, the variation of liposoluble vitamin, the variation of weight, the variation of body mass index With the variation of EPI symptoms.
Compared with those patients for receiving placebo, inhaled with the patient of these composition treatments in fat absorption coefficient and nitrogen Show increase statistically significantly in terms of receiving coefficient, and with less with impaired absorption (impaired Absorption) relevant symptom (such as aerogastria (bloating), flatulence (flatulence), pain and excrement (stool) fatty sign in).Compared with placebo, it is also observed in the patient for taking these pancreatic lipase compositions flat The increase of equal cholesterol levels and the increase of average vitamin level.It has been obtained statistically significantly in terms of daily stool interval Reduction.These compositions are well tolerable for patient, and are not observed during research relevant with drug Any serious adverse events.
Compared in the patient for receiving placebo 62.76% average fat absorption coefficient percentage, receive these compositions Patient in average fat absorption coefficient percentage be 88.28%.65.7% average nitrogen is inhaled in patient with receiving placebo It receives coefficient percentage to compare, average nitrogen absorption coefficient percentage is 87.2% and the average daily defecation for each patient's group Number is 2.66 to 1.77.
Embodiment 13
Paediatrics III clinical trial phases are carried out, so as to study (open- in open label in 11 CF therapeutic communities in the U.S. Label study) in the case of in patient of 19 ages below 7 years old the composition of evaluation table 34 therapeutic effect-this The replacement therapy of the pancreas for the first time experiment (pancreatic replacement therapy trial) of scale is outside with pancreas It is carried out in Secretion incomplete child and baby.Research and design includes seven days dose stability phases and seven days subsequent treatment phases； Patient receives 5 daily, 000 lipase unit/capsule, wherein product is sprinkled upon on food on demand.The Primary endpoint of research is The percentage of " respondent (responder) " does not have excessive fatty in one week treatment and after two weeks excrement and does not inhale Receive those patients of undesirable S＆S.It is thick that secondary endpoints include weight change, nutritional status, stool interval and excrement Degree, the incidence of the incidence of gaseous distention, the incidence of pain and ventosity and doctor and parent or guardian are to clinic The judgement that symptom improves.Product Safety is also evaluated.
(stationary phase starts i.e. when patient starts to connect in screening for average respondent's percentage defined in research approach By during previous pancreatin replacement therapy and before the treatment) it is 52.6%.At the end of stationary phase terminates with treatment phase, average response Person's percentage is respectively 66.4% and 57.9%.In the children studied, the malabsorption symptom at the end for the treatment of phase is notable Ground is less than the malabsorption symptom in screening, this is related with what is shown in being tested in the III phases described in above example 12 to inhaling It is consistent to receive the observation result that ill symptoms are controlled.The pancreatic lipase composition of the present invention is also resistance to well by these patients By, and be not observed and the relevant any serious adverse events of drug during experiment.
The results show that the composition of the present invention has efficiently controlled the S＆S of malabsorption and has supported and implemented Obtained result during the key III phases described in example 12 test.The doctor of notable ratio and the patient feels are to previous therapy It compares, the control carried out with the composition of the present invention to symptom is improved.
Embodiment 14
It is single at random that III phases open label is carried out in 10 Patients With Chronic Pancreatitis with pancreatic exocrine insufficiency Center singly treatment crossing research with the therapeutic effect of the pancreatic lipase composition of comparison sheet 34, so that it is determined that these compositions into Stomach and intestine availability under the conditions of food.Repellency drug (exclusionary drug) (proton pump inhibitor (PPI ' s), antacids With the drug that can change GI motilities) it is discontinued 7 days, subsequently into research.In each operation, patient receives independent at random Ensure PlusTM(the vitamin enrichment nutritional supplement for deriving from Abbott) or Ensure PlusTMWith 75,000USP fat The combination of enzyme unit (3 capsules respectively containing 20,000 units are plus 3 capsules respectively containing 5000 units).Capsule is beaten It opens, and before administration just to their content and 480mL Ensure PlusTMIt is mixed.In one day removing phase After (washout period), this operation is repeated, the difference is that previously-accepting independent Ensure PlusTMPatient receive Ensure PlusTMWith the combination of 75,000USP lipase units, and previously-accepting Ensure PlusTMIt is combined with lipase Patient receives individual Ensure PlusTM.At second day, patient received physical examination, and collects blood sample and urine sample.The present invention The bioavilability of composition passes through in Ensure PlusTMIn the presence of the composition is administered after discharged in duodenum It is assessed with the amounts of the various enzymes (i.e. lipase, amylase and chymotrypsin) of recycling.Also measure the gallbladder contraction in blood Plain (cholecystokinin) level and stomach and duodenal pH.Lipase active is surveyed according to the method for documents below Amount：Carriere,F,;Barrowman,J.A.;Verger,R.;Laugier,R.Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans.Gastroenterology1993,105,876-88.Amylase and chymotrypsin are according to the side described in documents below Method measures：Carriere,F.;Grandval,P.;Renou,C.;Palomba,A.;Prieri,F.;Giallo,J; Henniges,F.;Sander-Struckmeier,S.;Laugier,R.Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis Clin.Gastroenterol.Hepatol.2005,3,28-38。
It was found that cause following result with the treatment that the pancreatic lipase composition of the present invention carries out：With only receiving Ensure PlusTMPatient compare, receiving Ensure PlusTMThe starch discharged in the duodenum of the patient combined with pancreatic lipase The amount of the amount of enzyme, the amount of lipase and chymotrypsin be statistically significantly it is larger (with regard to pH (as confounding factor (confounding factor)) for be corrected after).
Mean bioavailability point of eight patients to lipase, amylase and chymotrypsin of research is completed according to scheme It Wei 27.5%, 21.6% and 40.1%.It was found that patient is divided into two kinds of different GI pH subgroups (" normal pH " and " low pH ").For For patient's (the duodenum pH that is averaged is more than 4 patient) with " normal pH " value, the mean bioavailability of lipase, The mean bioavailability of amylase and the mean bioavailability of chymotrypsin are higher than entire seminar：Respectively 45.6%, 26.9% and 47.7%.Any difference in terms of cholecystokinin value is not observed between two kinds of treatments.
Since for " normal pH " and " low pH " patient, the bioavilability of lipase, the biological utilisation of amylase The bioavilability of degree and chymotrypsin (the particularly bioavilability of lipase) is different, so can pass through co-administered Increase the drug (such as PPI ' s and antacids) of GI pH improve the effect of pancreatic lipase composition of the present invention or dosage form (such as In " low pH " patient).However, the composition or dosage form of the present invention can come in the case of no co-administered such as PPI ' s Administration.
For purposes of illustration and description, previous description for the present invention is had been provided for.It is not intended to exclusion or will The present invention is limited to disclosed concrete forms.According to the above instruction, modifications and variations are possible.In order to explain and describe this The principle and its practical application of invention, select the description in relation to embodiment, and are not intended to the model to claim It encloses and is limited.
The all publications and patents or patent application that the application is quoted are incorporated by reference with identical degree, Indicated clearly and that individually it is incorporated as reference just as every individual publication, patent or patent application Equally.

Claims (113)

1. a kind of composition for including a variety of coated particles, it includes pancreatic lipase and at least one pharmaceutical excipient, institutes It states coated particle and includes enteric-coated core, the core includes pancreatic lipase；The enteric coating includes at least one Kind enteric polymer and at least one inorganic material, wherein the enteric polymer and inorganic material are with 4:1 to 1:25 Ratio exist, wherein at least one excipient be selected from adhesive, disintegrant, lubricant, glidant, diluent and they Mixture, wherein the composition has 3% or smaller water capacity, and wherein described coated particle is with following It is coated in the atmosphere of water content：4g/m3Or smaller；
Wherein described enteric polymer be selected from Cellacefate, Hydroxypropyl Methylcellulose Phathalate, Hydroxypropylmethylcellulose acetate succinate, poly- acetate phthalate vinyl acetate, methacrylic acid-methyl methacrylate are common Polymers and shellac；
Wherein described at least one inorganic material includes basifier, the basifier be selected from talcum, silica, sodium salt, calcium salt, Magnesium salts, aluminium salt, aluminium hydroxide, calcium hydroxide, magnesium hydroxide and their mixture；
Wherein described coating also comprising plasticizer, the plasticizer be selected from glyceryl triacetate, tributyl citrate, triethyl citrate, Acetyl tributyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, One ester of acetylated glycerol, acetylated diglycerides and their mixture.
2. the composition of claim 1, wherein the water capacity is 2% or smaller.
3. the composition of claim 1, wherein the pancreatic lipase includes lipase.
4. the composition of claim 3, wherein the lipase is animal tallow enzyme, comprising lipase of bacterial origin, fungal lipase, plant Lipase, recombinant lipase, synthetic lipase, the lipase through chemical modification or their mixture.
5. the composition of claim 1, wherein at least one pharmaceutical excipient is selected from following at least one stabilizer： Trehalose, proline, glucan, maltose, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and their mixing Object.
6. the composition of claim 1, wherein at least one pharmaceutical excipient is selected from following at least one adhesive： Starch, sugar, sugar alcohol, cellulose, alginic acid and polyvinylpyrrolidone.
7. the composition of claim 1, wherein at least one pharmaceutical excipient is selected from following at least one adhesive： Lactose, xylitol, D-sorbite, maltitol, microcrystalline cellulose, modified cellulose, hydroxypropyl cellulose and carboxymethyl cellulose Plain sodium.
8. the composition of claim 1, wherein at least one pharmaceutical excipient is selected from following at least one disintegrant： Calcium monohydrogen phosphate, dicalcium phosphate dihydrate, calcium phosphate, cornstarch, alginic acid, hydroxypropyl cellulose, calcium carboxymethylcellulose, Sodium carboxymethylcellulose, croscarmellose sodium, swellable ion exchange resin, alginate, formaldehyde-casein, fibre Tie up element, cross-linked carboxymethyl cellulose sodium, Crospovidone, microcrystalline cellulose, sodium carboxymethyl starch, sodium starch glycollate, starch and Rice starch.
9. the composition of claim 1, wherein at least one pharmaceutical excipient is selected from following at least one lubricant： Calcium stearate, magnesium stearate, Sodium stearyl fumarate, stearic acid, zinc stearate, talcum and wax.
10. the composition of claim 1, wherein at least one pharmaceutical excipient is to help stream selected from following at least one Agent：Colloidal silicon dioxide and talcum.
11. the composition of claim 1, wherein at least one pharmaceutical excipient is selected from following at least one dilution Agent：Mannitol, sucrose, calcium phosphate dibasic anhydrous, calcium phosphate dibasic anhydrous dihydrate, calcium phosphate, cellulose, lactose, magnesium carbonate and Microcrystalline cellulose.
12. the composition of claim 1, wherein under accelerated stability test, the composition is more than 3% group with water capacity It closes object and compares the larger stability for showing lipase active.
13. the composition of claim 1, wherein the core is the small pieces of particle size range 2-5mm.
14. the composition of claim 1, wherein the core is the small pieces of particle size range 1-2mm.
15. the composition of claim 1, wherein the composition has 1.5% to 2.5% water capacity.
16. the composition of claim 1, wherein the composition has 2% water capacity.
17. the composition comprising at least one digestive ferment and at least one pharmaceutical excipient, said composition is coated particle, Wherein described composition has 0.6 or smaller water activity, wherein at least one pharmaceutical excipient is selected from adhesive, disintegration Agent, lubricant, glidant, diluent and their mixture, the coated particle include enteric-coated core, institute It states core and includes at least one digestive ferment；The enteric coating includes at least one enteric polymer and at least one inorganic material Material, wherein the enteric polymer and inorganic material are with 4:1 to 1:25 ratio exists, wherein the composition has 3% Or smaller water capacity, and wherein described coated particle is coated in the atmosphere with following water content：4g/m3Or more It is small；
Wherein described enteric polymer be selected from Cellacefate, Hydroxypropyl Methylcellulose Phathalate, Hydroxypropylmethylcellulose acetate succinate, poly- acetate phthalate vinyl acetate, methacrylic acid-methyl methacrylate are common Polymers and shellac；
Wherein described at least one inorganic material includes basifier, the basifier be selected from talcum, silica, sodium salt, calcium salt, Magnesium salts, aluminium salt, aluminium hydroxide, calcium hydroxide, magnesium hydroxide and their mixture；
Wherein described coating also comprising plasticizer, the plasticizer be selected from glyceryl triacetate, tributyl citrate, triethyl citrate, Acetyl tributyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, One ester of acetylated glycerol, acetylated diglycerides and their mixture.
18. the composition of claim 17, wherein water activity is 0.4 or smaller.
19. the composition of claim 17, wherein at least one digestive ferment is selected from pancreatic lipase, trypsase, rotten albumen Enzyme, pancreas peptase, Carboxypeptidase A, protaminase, glycerol ester hydrolase, phosphatidase, sterol ester hydrolase, ribalgilase, deoxidation core Ribonuclease T., papain, chymopapain, bromelain, ficin, cellulase, beta galactose Glycosides enzyme and their mixture.
20. the composition of claim 17, wherein at least one digestive ferment is selected from lipase, chymotrypsin B, phospholipase A2、 Alpha-amylase and beta amylase.
21. the composition of claim 20, wherein at least one digestive ferment is lipase.
22. the composition of claim 19, wherein at least one digestive ferment is pancreatic lipase.
23. the composition of claim 21, wherein the lipase is animal tallow enzyme, comprising lipase of bacterial origin, fungal lipase, plant Object lipase, recombinant lipase, synthetic lipase, the lipase through chemical modification or their mixture.
24. the composition of claim 17, wherein at least one pharmaceutical excipient is to stablize selected from following at least one Agent：Trehalose, proline, glucan, maltose, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and they Mixture.
25. the composition of claim 17, wherein at least one pharmaceutical excipient is selected from following at least one bonding Agent：Starch, sugar, sugar alcohol, cellulose, alginic acid and polyvinylpyrrolidone.
26. the composition of claim 17, wherein at least one pharmaceutical excipient is selected from following at least one bonding Agent：Lactose, xylitol, D-sorbite, maltitol, microcrystalline cellulose, modified cellulose, hydroxypropyl cellulose and carboxymethyl are fine The plain sodium of dimension.
27. the composition of claim 17, wherein at least one pharmaceutical excipient is selected from following at least one disintegration Agent：Calcium monohydrogen phosphate, dicalcium phosphate dihydrate, calcium phosphate, cornstarch, alginic acid, hydroxypropyl cellulose, carboxymethyl cellulose Calcium, sodium carboxymethylcellulose, croscarmellose sodium, swellable ion exchange resin, alginate, formaldehyde-casein, Cellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, microcrystalline cellulose, sodium carboxymethyl starch, sodium starch glycollate, starch And rice starch.
28. the composition of claim 17, wherein at least one pharmaceutical excipient is selected from following at least one lubrication Agent：Calcium stearate, magnesium stearate, Sodium stearyl fumarate, stearic acid, zinc stearate, talcum and wax.
29. the composition of claim 17, wherein at least one pharmaceutical excipient is to help stream selected from following at least one Agent：Colloidal silicon dioxide and talcum.
30. the composition of claim 17, wherein at least one pharmaceutical excipient is selected from following at least one dilution Agent：Mannitol, sucrose, calcium phosphate dibasic anhydrous, calcium phosphate dibasic anhydrous dihydrate, calcium phosphate, cellulose, lactose, magnesium carbonate and Microcrystalline cellulose.
31. the composition of claim 17, wherein at least one stabilizer is selected from trehalose, proline, glucan, malt Sugar, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and their mixture.
32. the composition of claim 17, wherein under accelerated stability test, the composition is more than 0.6 with water activity Composition compares the larger stability for showing lipase active.
33. the composition of claim 17, wherein the core is the small pieces of particle size range 2-5mm.
34. the composition of claim 17, wherein the core is the small pieces of particle size range 1-2mm.
35. the composition of claim 17, wherein the composition is with 0.2 to 0.6 water activity.
36. the composition of claim 17, wherein the composition is with 0.3 water activity.
37. the composition comprising at least one digestive ferment and at least one pharmaceutical excipient, said composition is coated particle, Wherein described at least one digestive ferment shows the digestive enzyme activity no more than 15% after the accelerated stability test of six months Loss, wherein at least one pharmaceutical excipient be selected from adhesive, disintegrant, lubricant, glidant, diluent and they Mixture, the coated particle include enteric-coated core, and the core includes at least one digestive ferment；The intestines Molten clothing includes at least one enteric polymer and at least one inorganic material, wherein the enteric polymer and inorganic material With 4:1 to 1:25 ratio exists, wherein the composition has 3% or smaller water capacity, and it is wherein described coated Particle be coated in the atmosphere with following water content：4g/m3Or smaller；
Wherein described enteric polymer be selected from Cellacefate, Hydroxypropyl Methylcellulose Phathalate, Hydroxypropylmethylcellulose acetate succinate, poly- acetate phthalate vinyl acetate, methacrylic acid-methyl methacrylate are common Polymers and shellac；
Wherein described at least one inorganic material includes basifier, the basifier be selected from talcum, silica, sodium salt, calcium salt, Magnesium salts, aluminium salt, aluminium hydroxide, calcium hydroxide, magnesium hydroxide and their mixture；
Wherein described coating also comprising plasticizer, the plasticizer be selected from glyceryl triacetate, tributyl citrate, triethyl citrate, Acetyl tributyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, One ester of acetylated glycerol, acetylated diglycerides and their mixture.
38. the composition of claim 37, wherein at least one digestive ferment is shown after trimestral accelerated stability test Show that the digestive enzyme activity no more than 10% loses.
39. the composition of claim 37, wherein the accelerated stability test is included in 40 DEG C/75% relative humidity by described in Composition is stored 3 months in the Nialene bags of sealing.
40. the composition of claim 37, wherein at least one digestive ferment is selected from pancreatic lipase, trypsase, rotten albumen Enzyme, pancreas peptase, Carboxypeptidase A, protaminase, glycerol ester hydrolase, phosphatidase, sterol ester hydrolase, ribalgilase, deoxidation core Ribonuclease T., papain, chymopapain, bromelain, ficin, cellulase, beta galactose Glycosides enzyme and their mixture.
41. the composition of claim 37, wherein at least one digestive ferment is selected from lipase, chymotrypsin B, phospholipase A2、 Alpha-amylase and beta amylase.
42. the composition of claim 41, wherein at least one digestive ferment is lipase.
43. the composition of claim 40, wherein at least one digestive ferment is pancreatic lipase.
44. the composition of claim 42, wherein the lipase is animal tallow enzyme, comprising lipase of bacterial origin, fungal lipase, plant Object lipase, recombinant lipase, synthetic lipase, the lipase through chemical modification or their mixture.
45. the composition of claim 37, wherein at least one pharmaceutical excipient is to stablize selected from following at least one Agent：Trehalose, proline, glucan, maltose, sucrose, mannitol, polyalcohol, silica gel, aminoguanidine, Pyridoxamine and they Mixture.
46. the composition of claim 37, wherein at least one pharmaceutical excipient is selected from following at least one bonding Agent：Starch, sugar, sugar alcohol, cellulose, alginic acid and polyvinylpyrrolidone.
47. the composition of claim 37, wherein at least one pharmaceutical excipient is selected from following at least one bonding Agent：Lactose, xylitol, D-sorbite, maltitol, microcrystalline cellulose, modified cellulose, hydroxypropyl cellulose and carboxymethyl are fine The plain sodium of dimension.
48. the composition of claim 37, wherein at least one pharmaceutical excipient is selected from following at least one disintegration Agent：Calcium monohydrogen phosphate, dicalcium phosphate dihydrate, calcium phosphate, cornstarch, alginic acid, hydroxypropyl cellulose, carboxymethyl cellulose Calcium, sodium carboxymethylcellulose, croscarmellose sodium, swellable ion exchange resin, alginate, formaldehyde-casein, Cellulose, cross-linked carboxymethyl cellulose sodium, Crospovidone, microcrystalline cellulose, sodium carboxymethyl starch, sodium starch glycollate, starch And rice starch.
49. the composition of claim 37, wherein at least one pharmaceutical excipient is selected from following at least one lubrication Agent：Calcium stearate, magnesium stearate, Sodium stearyl fumarate, stearic acid, zinc stearate, talcum and wax.
50. the composition of claim 37, wherein at least one pharmaceutical excipient is to help stream selected from following at least one Agent：Colloidal silicon dioxide and talcum.
51. the composition of claim 37, wherein at least one pharmaceutical excipient is selected from following at least one dilution Agent：Mannitol, sucrose, calcium phosphate dibasic anhydrous, calcium phosphate dibasic anhydrous dihydrate, calcium phosphate, cellulose, lactose, magnesium carbonate and Microcrystalline cellulose.
52. a kind of dosage form, tablet or capsule including the composition containing claim 1.
53. the dosage form of claim 52, wherein the dosage form is the capsule of the composition filled with claim 1.
54. the dosage form of claim 53, it includes：
There are many capsules of coated particle for filling；
The coated particle includes enteric-coated core；
The core includes pancreatic lipase and at least one disintegrant；And
The enteric coating includes at least one enteric polymer and is at least the one of 20-60%wt.% based on coating total weight Kind basifier；
There is wherein described coated particle 3% or smaller water capacity and the capsule to have 4% or smaller containing wet Amount.
55. the dosage form of claim 54, wherein the capsule has 2% or smaller water capacity.
56. the dosage form of claim 53, wherein the capsule is formed by being selected from following substance：Cellulosic polymer, hydroxypropyl Methylcellulose, starch, polysaccharide, pullulan and gelatin.
57. the dosage form of claim 56, wherein the capsule includes hydroxypropyl methyl cellulose.
58. the dosage form of claim 54, wherein the capsule includes hydroxypropyl methyl cellulose.
59. a kind of dosage form includes the capsule of the composition filled with claim 17.
60. the dosage form of claim 59, wherein the capsule has 2% or smaller water content.
61. the dosage form of claim 59, wherein the capsule is formed by being selected from following substance：Cellulosic polymer, hydroxypropyl Methylcellulose, starch, polysaccharide, pullulan and gelatin.
62. the dosage form of claim 61, wherein the capsule includes hydroxypropyl methyl cellulose.
63. a kind of dosage form includes the capsule of the composition filled with claim 37.
64. the dosage form of claim 63, wherein the capsule has the water content less than 2%.
65. the dosage form of claim 63, wherein the capsule is formed by being selected from following substance：Cellulosic polymer, hydroxypropyl Methylcellulose, starch, polysaccharide, pullulan and gelatin.
66. the dosage form of claim 65, wherein the capsule includes hydroxypropyl methyl cellulose.
67. the dosage form of claim 53, wherein the capsule has 2% or smaller water capacity.
68. the dosage form of claim 52, wherein the capsule has the water capacity less than 4%.
69. the dosage form of claim 56, wherein the capsule has the water capacity less than 2%.
70. a kind of packaging, it includes the sealing container being made of barrier material, drier and at least one claim 52 Dosage form, wherein the drier and at least one dosage form are in the sealed container interior.
71. the packaging of claim 70, wherein the barrier material is selected from metal, glass, plastics and the plastics coated with metal.
72. the packaging of claim 70, wherein the drier is selected from molecular sieve, clay, silica gel, activated carbon and their group It closes.
73. the packaging of claim 72, wherein the drier is molecular sieve.
74. a kind of packaging, it includes the sealing container being made of barrier material, drier and at least one claim 59 Dosage form, wherein the drier and at least one dosage form are in the sealed container interior.
75. the packaging of claim 74, wherein the barrier material is selected from metal, glass, plastics and the plastics coated with metal.
76. the packaging of claim 74, wherein the drier is selected from molecular sieve, clay, silica gel, activated carbon and their group It closes.
77. the packaging of claim 76, wherein the drier is molecular sieve.
78. a kind of packaging, it includes the sealing container made of barrier material, drier and at least one claim 63 Dosage form, wherein the drier and at least one dosage form are in the sealed container interior.
79. the packaging of claim 78, wherein the barrier material is selected from metal, glass, plastics and the plastics coated with metal.
80. the packaging of claim 78, wherein the drier is selected from molecular sieve, clay, silica gel, activated carbon and their group It closes.
81. the packaging of claim 80, wherein the drier is molecular sieve.
82. the composition of claim 1 is lacked in preparation for being treated or prevented in the mammal for having this to need with digestive ferment Purposes in the drug of weary relevant illness.
83. the composition of claim 17 is lacked in preparation for being treated or prevented in the mammal for having this to need with digestive ferment Purposes in the drug of weary relevant illness.
84. the composition of claim 37 is lacked in preparation for being treated or prevented in the mammal for having this to need with digestive ferment Purposes in the drug of weary relevant illness.
85. the drug of the composition of claim 1 and raising gastrointestinal tract pH are being prepared in the mammal for having this to need Treatment or prevention and the purposes in the drug of the digestion relevant illness of azymia, wherein the treatment or prevention include right is administered It is required that 1 composition and the drug of raising gastrointestinal tract pH.
86. the purposes of claim 85, wherein the drug for improving gastrointestinal tract pH is selected from proton pump inhibitor and antacids.
87. the purposes of claim 85, wherein the administration include giving the dosage form of the composition comprising claim 1 and comprising Improve another dosage form of the drug of gastrointestinal tract pH.
88. the purposes of claim 85, wherein the administration includes giving the composition comprising claim 1 and improves gastrointestinal tract The single formulation of the drug of pH.
89. the method for the composition of claim 1 is prepared, the described method includes：
It is 4g/m in water capacity3Or with the coating pair comprising enteric polymer and at least one inorganic material in smaller atmosphere The particle of pancreatic lipase is coated, and is consequently formed a variety of delayed release granules.
90. the method for claim 89, wherein the water capacity of the atmosphere is 3.6g water/m3Or smaller.
91. the method for claim 89, wherein the atmosphere includes air, nitrogen or inert gas.
92. the method for claim 89, wherein mixed at least one inorganic material and the enteric polymer being dissolved in acetone Object is closed to be coated the particle of pancreatic lipase.
93. the method for the composition of claim 17 is prepared, the described method includes：
It is 4g/m in water capacity3Or with the coating pair comprising enteric polymer and at least one inorganic material in smaller atmosphere The particle of at least one digestive ferment is coated, and is consequently formed a variety of sustained release dosage units.
94. the method for claim 93, wherein the water capacity of the atmosphere is 3.6g water/m3Or smaller.
95. the method for claim 93, wherein the atmosphere includes air, nitrogen or inert gas.
96. the method for claim 93, wherein mixed at least one inorganic material and the enteric polymer being dissolved in acetone Object is closed to be coated the particle of digestive ferment.
97. the method for the composition of claim 37 is prepared, the described method includes：
It is 4g/m in water capacity3Or with the enteric coating comprising enteric polymer and at least one inorganic material in smaller atmosphere The particle of at least one digestive ferment is coated, is consequently formed a variety of sustained release dosage units.
98. the method for claim 97, wherein the water capacity of the atmosphere is 3.6g water/m3Or smaller.
99. the method for claim 97, wherein the atmosphere includes air, nitrogen or inert gas.
100. the method for claim 97, wherein mixed at least one inorganic material and the enteric polymer being dissolved in acetone Object is closed to be coated the particle of digestive ferment.
101. the method for the composition of claim 1 is prepared, the described method includes：
The composition of pancreatic lipase is included described in preparing, wherein the composition has 3% or smaller water capacity.
102. the method for the composition of claim 17 is prepared, the described method includes：
The composition of at least one digestive ferment is included described in preparing, wherein the composition has 0.6 or smaller water activity.
103. the method for the composition of claim 37 is prepared, the described method includes：
The composition of at least one digestive ferment is included described in preparing, wherein accelerated stability test of the digestive ferment at six months The loss of activity no more than 15% is shown afterwards.
104. the composition of claim 17 or 37, wherein at least one digestive ferment is pancreatic lipase.
105. the composition of claim 1 or 104, wherein the pancreatic lipase is from pig.
106. a kind of dosage form, wherein the dosage form is zero dosage form excessively filled of the composition comprising claim 105.
107. the composition of claim 105 is being prepared for treating pancreatic exocrine insufficiency in patient in need Drug in purposes.
108. the purposes of claim 107, wherein the patient suffers from cystic fibrosis.
109. the purposes of claim 107, wherein the fat absorption that the treatment mitigates in the patient is bad.
110. the purposes of claim 107, wherein the treatment increases the fat absorption coefficient in the patient.
111. the purposes of claim 108, wherein the treatment increases fat absorption coefficient in the patient at least 85%.
112. the purposes of claim 110, wherein the increase of fat absorption coefficient is in no co-administered in the patient Occur in the case of proton pump inhibitor.
113. including the composition of a variety of coated particles, each described particle includes enteric-coated core；Wherein institute Core is stated to include：
Pancreatic lipase；
At least one polymer adhesive；
At least one disintegrant；
At least one lubricant；
At least one glidant；With
At least one plasticizer；And
Wherein described enteric coating includes：
At least one enteric polymer of 10-20%wt.%；With
The talcum of 4-10%wt.%；
Wherein each total weights of wt.% based on coated particle；
Wherein described composition has 3% or smaller water capacity, and wherein described coated particle with containing below It is coated in the atmosphere of water：4g/m3Or smaller；
Wherein described enteric polymer be selected from Cellacefate, Hydroxypropyl Methylcellulose Phathalate, Hydroxypropylmethylcellulose acetate succinate, poly- acetate phthalate vinyl acetate, methacrylic acid-methyl methacrylate are common Polymers and shellac；
The plasticizer is selected from glyceryl triacetate, tributyl citrate, triethyl citrate, acetyl tributyl citrate, adjacent benzene Dicarboxylate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, one ester of acetylated glycerol, acetylated glycerol Diester and their mixture.
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